2-oxoquinoline compounds and pharmaceutical uses thereof

ABSTRACT

A 2-oxoquinoline compound or its pharmaceutically acceptable salt of general formula [I]:  
                 
 
     (wherein each symbol in the formula is as determined in the description), and its pharmaceutical use.  
     The compound [I] of the present invention and its pharmaceutically acceptable salts selectively act on cannabinoid receptors, particularly on peripheral type cannabinoid receptors, and have fewer side effects on the central nervous system, having great immunosuppressive action, anti-inflammatory action or antiallergic action. Therefore, these compounds are useful as cannabinoid receptors (particularly peripheral type cannabinoid receptors) modulator, immunosuppressants, anti-inflammatory agents, and antiallergic agents.

TECHNICAL FIELD

[0001] The present invention relates to novel 2-oxoquinoline compoundsand pharmaceutical uses thereof. In addition, the invention relates tonovel uses of some types of 2-oxoquinoline compounds. More specifically,the invention relates to novel 2-oxoquinoline compounds that selectivelyact on cannabinoid receptors, particularly on peripheral cannabinoidreceptors, and that have immunomodulating action, anti-inflammatoryaction, and antiallergic action with fewer side effects on the centralnervous system and to pharmaceutical uses thereof.

BACKGROUND ART

[0002] So far, a series of compounds named cannabinoids, which compriseC, H, and O, are known as constituents of cannabis. It has also beenknown that, among them, tetrahydrocannabinol (THC) is a majorhallucinogen, and that a principal ingredient contained in the cannabisplant is Δ9-THC. It has been reported that Δ9-THC has actions includingataxia, increased sensitivity to stimulation, antiemetic action,analgesic action, hypothermic action, respiratory depression,catalepsy-inducing action, vasodilator action, immunosuppressive action,etc.

[0003] The sites of these actions of Δ9-THC are roughly categorized intothe central nervous system (Devane et al., Mol Pharmacol. 1988, 34,605-613; Hollister et al., Pharmacol. Rev., 1986, 38, 1-20; Renu et al.,Prog. Drug Res., 1991, 36, 71-114) and the peripheral tissues (Nye etal., J. Pharmacol. Exp. Ther., 1985, 234, 784-791; Flynn et al., MolPharmacol. 1992, 41, 736-742). There are reports suggesting that some ofthe actions on the central nervous system are medically applicable.

[0004] On the other hand, it has been found that there exists theperipheral type receptor, for example, the receptor on macrophages(Munnro et al., Nature, 1993, 365, 61-65). Based on this finding,research and development are being carried out with the objective ofdesigning peripheral type receptor agonists capable of modulating immunereaction and having anti-inflammatory action, antiallergic action, aswell as the original immunomodulating action.

[0005] Further, agents selectively acting on peripheral type cannabinoidreceptors can be safe agents that have no side effects on the centralnervous system such as hypothermic action, catalepsy, and such, andtherefore modulators selective for the peripheral type receptor areexpected to be developed in particular.

[0006] Known cannabinoid receptor agonists include pyrazole derivatives(Unexamined Published Japanese Patent Application (JP-A) No. Hei6-73014; EP Nos. 656354 and 658546), THC derivatives (JP-A Hei3-209377), benzoxazine derivatives (U.S. Pat. No. 5,112,820), indolederivatives (U.S. Pat. No. 5,081,122), and aliphatic acid derivatives(WO 94/12466). However, there have previously been no findings on2-oxoquinoline compounds by which the compounds of the present inventionare characterized.

[0007] On the other hand, a variety of quinoline derivatives have beenreported in terms of chemical structure.

[0008] For example, a reference of J. Pharm. Sci., 73, 11, 1652-1653(1984) describes 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid benzylamide (compound A shown below), which is useful as astimulant for the central nervous system. Another reference, Khim.Geterotsikl. Soedin., 8, 1101-1104 (1993), describes4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(pyridine-2-yl)amide (compound B shown below), which is useful as ananti-inflammatory agent. In Pharmaproject and others, it has beenreported that 4-hydroxy-2-oxo-1-methyl-1,2-dihydroquinoline-3-carboxylicacid N-methyl-N-phenylamide (compound C shown below) that is also called“roquinimex” can be used as agents for a variety of diseases, e.g.,anti-inflammatory agent, immunosuppressant, and antirheumatic agent.

[0009] Further, Examined Japanese Patent Publication No. Sho 47-14107discloses a method for synthesizing3-benzoylamino-6,7-dimethoxy-2-(1H)quinolone (compound D shown below)that can be used as an agent acting on the central nervous system.

[0010] In addition, 2-oxo-1,2-dihydroquinoline-3-carboxylic acidcyclohexylamide has been disclosed in synthesis, 11, 1362-1364 (1995).Quinoline compounds which are useful as immunomodulators have beendisclosed in Published Japanese Translation of International PublicationNo. Hei 4-500373. Quinoline compounds which are useful as analgesicagents have been disclosed in French Patent Publication No. 2377400.Quinoline compounds which are useful as 5-HT₄ receptor agonists havebeen disclosed in republished patent publication WO 96/05166.

[0011] Further, one of 2-oxoquinoline compounds having3,4-methylenedioxyphenyl group, which is one of specific features of thecompounds of the present invention, isN-(3,4-methylenedioxyphenyl)-1,2-dihydro-4-hydroxy-l-methyl-2-oxoquinoline-3-carboxamide(compound E shown below), which is a compound capable of enhancingimmunological activities and has been disclosed in JP-A Sho 57-171975(EP No. 59698). Yet further,1-methyl-2-oxo-3-(N-(1,3-benzodioxole-5-yl)-N-methylcarbamoyl)-4-hydroxy-6-methylthio-1,2-dihydroquinoline(compound F shown below), which has immunomodulating action,anti-inflammatory action, and analgesic action, has been disclosed inPublished Japanese Translation of International Publication No. Hei6-506925 (WO 92/18483).

[0012] However, these references have no description suggesting theexistence of 2-oxoquinoline compounds of the present invention norsuggestion of pharmacological action based on the cannabinoidreceptor-mediated mechanism.

[0013] On the other hand, description found in the publication of WO97/29079 is that some compounds having quinoline structure, functioningas cannabinoid receptor agonist or antagonist, are useful asimmunomodulators, anti-inflammatory agents, antiallergic agents, or thelike.

[0014] However, the quinoline compounds disclosed in the reference aremerely quinolines that have been substituted with a hydroxy, and in thereference, there is no description suggesting the existence of the2-oxoquinoline compounds of the present invention.

[0015] A reference of JP-A Hei 11-80124 (WO 99/02499) also describesimmunomodulator, anti-inflammatory agent, and antiallergic agentcomprising cannabinoid receptor agonist or antagonist as an activeingredient. The patent publication has also disclosed7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-aminophenyl)amide (compound G) and such, which is one of compoundshaving the 2-oxoquinoline structure that is one of specific features ofthe compounds of the present invention.

[0016] In more detail, in the above-mentioned patent publication, forexample, just merely the above-mentioned compound G and three othercompounds are specifically disclosed, and the reference has nodescription of the inventive compounds that disclosed herein, which isrepresented by general formula [I], including compounds of which R^(a)is alkyl; compounds of which X is —COOR^(b), —CONH₂, —(CH₂)_(p)—OC(═Y)—NR^(d)-(Alk^(b))_(g)—R,—(CH₂)_(q)—NR^(e)—C(=Z)-(NR^(f))_(w)-(Alk^(c))_(v)—R, —(CH_(z))_(p)—OH,or —(CH_(z))_(q)—NR^(e)R^(e)′ (where each symbol is as defined herein);compounds of which X is —CONR^(c)-(Alk^(a))_(r)—R and R^(c) is alkyl; orcompounds of which R is represented by:

[0017] where each symbol is as defined herein.

[0018] It should be noted that, while the above-mentioned patentapplication was first laid open to public inspection on Jan. 21, 1999(WO 99/02499), the priority date of the present application is Jan. 8,1999, which is therefore earlier than the above publication date.

DISCLOSURE OF THE INVENTION

[0019] An objective of the present invention is to provide novelcompounds selectively acting on cannabinoid receptors, particularly onperipheral cannabinoid receptors and to provide pharmaceuticalcompositions thereof.

[0020] More specifically, the objective of the present invention is toprovide novel compounds and pharmaceutical compositions thereof that arecapable of selectively acting on cannabinoid receptors, particularly onthe receptors of peripheral tissues, and that have therapeutic effectsincluding immunomodulating action, anti-inflammatory action,antiallergic action, and such, but that hardly influence the centralnervous system (specifically, side effects such as excitation,hallucination, ataxia, increased sensitivity to stimulation,hypothermicaction, respiratory depression, catalepsy-inducing action,hypotention, etc.) and that are less toxic.

[0021] In order to achieve the above-mentioned objective, the presentinventors strenuously studied and then found 2-oxoquinoline compoundsexhibiting selective affinity for cannabinoid receptors, particularlyfor the peripheral type receptors, and thus being pharmaceuticallyuseful for diseases associated with cannabinoid receptors, particularlydiseases associated with peripheral type tissues (immune disease,various types of inflammation, allergic diseases, etc.). Thus, theinventors completed the present invention.

[0022] Specifically, the present invention comprises the following items(1)-(27):

[0023] (1) A cannabinoid receptor modulator comprising, as an activeingredient, a 2-oxoquinoline compound represented by the followinggeneral formula [I] or its pharmaceutically acceptable salt:

[0024] where

[0025] W means —O—, —S(O)_(t)—, —CR³R⁴—, —NR⁵—, —NR⁵CO—, —CONR⁵—, —COO—,or —OCO— (where R³ and R⁴ may be identical or different and representhydrogen atom or alkyl; R⁵ represents hydrogen atom or alkyl; and tindicates an integer, 0, 1 or 2);

[0026] R¹ represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;each group of R¹, except hydrogen atom, may be substituted orunsubstituted with alkylamino, amino, hydroxy, alkoxy, carboxy,alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio,alkylsulfinyl or alkylsulfonyl; each group, except hydrogen atom andalkyl, may be substituted or unsubstituted with alkyl;

[0027] R² represents hydrogen atom, alkyl, —OR⁶ (where R⁶ representshydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl or cycloalkylalkyl), —NR⁷R⁸ (where R⁷ and R⁸may be identical or different and represent hydrogen atom, alkyl,alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or cycloalkylalkyl; or R⁷ and R⁸, together with the adjacentnitrogen atom, can form a heteroaryl); or —(CH₂)_(u)′—S(O)_(u)R⁹ (whereR⁹ represents hydrogen atom, alkyl, alkenyl or alkynyl, each of u and u′independently represents an integer, 0, 1 or 2); each group of R²,except hydrogen atom, may be substituted or unsubstituted withalkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy,acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl; eachgroup, except hydrogen atom and alkyl, may be substituted orunsubstituted with alkyl;

[0028] R^(a) represents hydrogen atom or alkyl;

[0029] X represents —COOR^(b), —CONH₂, —CONR^(c)-(Alk^(a))_(r)—R,—(CH₂)_(p)—OC(═Y)—NR^(d)-(Alk^(b))_(a)-R,—(CH₂)_(q)—NR^(e)—C(=Z)-(NR^(f))_(w)-(Alk^(c))_(v)-R, —(CH₂)_(p)—OH or—(CH₂) _(q)—NR^(e)R^(e)′

[0030] (where each of R^(b), R^(c), R^(d), and R^(f) independentlyrepresents hydrogen atom or alkyl; each of R^(e) and R^(e)′independently represents hydrogen atom or alkyl; or R^(e) and R^(e)′,together with the adjacent nitrogen atom, can form a heteroaryl;

[0031] each of Alk^(a), Alk^(b) and Alk^(c) independently representsalkylene or alkenylene; each of the alkylene and alkenylene may besubstituted or unsubstituted with hydroxy, carboxy, alkoxycarbonyl,alkyl (the alkyl may be substituted or unsubstituted with hydroxy,alkoxy or alkylthio) or —CONR¹⁰R¹¹ (where R¹⁰ and R¹¹ may be identicalor different and represent hydrogen atom or alkyl; or R¹⁰ and R¹¹,together with the adjacent nitrogen atom, can form a heteroaryl);

[0032] R represents aryl, heteroaryl, cycloalkyl, benzene-condensedcycloalkyl or

[0033] where

[0034] A and B independently represent oxygen atom, nitrogen atom orsulfur atom; k indicates an integer of 1-3; each of the aryl andheteroaryl may be substituted or unsubstituted with an alkyl substitutedor unsubstituted with hydroxy or may be substituted or unsubstitutedwith a hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro,amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino,carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronicacid residue; the cycloalkyl may be substituted or unsubstituted with ahydroxy, alkoxy or ═O; the benzene-condensed cycloalkyl may besubstituted or unsubstituted with a hydroxy or alkoxy;

[0035] each of r, s, v and w independently represents 0 or 1; each of Yand Z independently represents a nitrogen atom, oxygen atom or sulfuratom; and each of p and q independently represents an integer of 1-4).

[0036] (2) A cannabinoid receptor modulator comprising, as an activeingredient, the 2-oxoquinoline compound of (1) or its pharmaceuticallyacceptable salt, wherein W represents —O—; R¹ is hydrogen atom or alkyl(the alkyl is as described above); R² represents —OR⁶ (R⁶ is asdescribed above); and R is aryl, heteroaryl or

[0037] where aryl, heteroaryl, and each symbol in the formula are asdefined above.

[0038] (3) A 2-oxoquinoline compound as represented by the followinggeneral formula [I′] or its pharmaceutically acceptable salt:

[0039] where

[0040] W means —O—, —S(O)_(t)—, —CR³R⁴—, —NR⁵—, —NR⁵CO—, —CONR⁵—, —COO—or —OCO— (where R³ and R⁴ may be identical or different and representhydrogen atom or alkyl; R⁵ represents hydrogen atom or alkyl; and tindicates an integer, 0, 1 or 2);

[0041] R¹ represents hydrogen atom, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl;each group of R¹, except hydrogen atom, may be substituted orunsubstituted with alkylamino, amino, hydroxy, alkoxy, carboxy,alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, alkylthio,alkylsulfinyl or alkylsulfonyl; each group, except hydrogen atom andalkyl, may be substituted or unsubstituted with alkyl;

[0042] R² represents hydrogen atom, alkyl, —OR⁶ (where R⁶ representshydrogen atom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl or cycloalkylalkyl), —NR⁷R⁸ (where R⁷ and R⁸may be identical or different and represent hydrogen atom, alkyl,alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or cycloalkylalkyl; or R⁷ and R⁸, together with the adjacentnitrogen atom, can form a heteroaryl); or —(CH₂)_(u)′—S(O)_(u)R⁹ (whereR⁹ represents hydrogen atom, alkyl, alkenyl or alkynyl, each of u and u′independently represents an integer, 0, 1 or 2) ; each group of R²,except hydrogen atom, may be substituted or unsubstituted withalkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy,acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl; eachgroup, except hydrogen atom and alkyl, may be substituted orunsubstituted with alkyl;

[0043] R^(a) represents hydrogen atom or alkyl;

[0044] X′ represents —CONR^(c)-(Alk^(a))_(r)-R,—(CH₂)_(p)—OC(═Y)—NR^(d)-(Alk^(b))-R or—(CH₂)_(q)—NR^(e)—C(=Z)-(NR^(f))_(w)-(Alk^(c))_(v)-R,

[0045] where each of R^(c), R^(d), R^(e) and R^(f) independentlyrepresents hydrogen atom or alkyl;

[0046] each of Alk^(a), Alk^(b)and Alk^(c) independently representsalkylene or alkenylene; each of the alkylene and alkenylene may besubstituted or unsubstituted with hydroxy, carboxy, alkoxycarbonyl,alkyl (the alkyl may be substituted or unsubstituted with a hydroxy,alkoxy or alkylthio);

[0047] or —CONR¹⁰R¹¹ (where R¹⁰ and R¹¹ may be identical or differentand represent hydrogen atom or alkyl; or R¹⁰ and R¹¹, together with theadjacent nitrogen atom, can form a heteroaryl);

[0048] R represents aryl, heteroaryl, cycloalkyl, benzene-condensedcycloalkyl or

[0049] where

[0050] A and B independently represent oxygen atom, nitrogen atom orsulfur atom; k indicates an integer of 1-3; each of the aryl andheteroaryl may be substituted or unsubstituted with an alkyl substitutedor unsubstituted with hydroxy or may be substituted or unsubstitutedwith a hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro,amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino,carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronicacid residue; the cycloalkyl may be substituted or unsubstituted with ahydroxy, alkoxy or ═O; the benzene-condensed cycloalkyl may besubstituted or unsubstituted with a hydroxy or alkoxy;

[0051] each of r, s, v and w independently represents 0 or 1; each of yand Z independently represents a nitrogen atom, oxygen atom or sulfuratom; and each of p and q independently represents an integer of 1-4,

[0052] provided that:

[0053] (a) when R² is a hydrogen atom, then WR¹ is substituted atposition-j of 2-oxoquinoline; and

[0054] (b)1,2-dihydro-6,7-dimethoxy-2-oxo-N-(phenylmethyl)-3-quinolinecarboxamideand N-(1,2-dihydro-6,7-dimethoxy-2-oxo-3-quinolyl)benzamide areexcluded.

[0055] (4) The 2-oxoquinoline compound of (3) or its pharmaceuticallyacceptable salt, wherein R^(a) is alkyl.

[0056] (5) The 2-oxoquinoline compound of (3) or its pharmaceuticallyacceptable salt, wherein X′ is —CONR^(c)-(Alk^(a))_(r)-R.

[0057] (6) The 2-oxoquinoline compound of (5) or its pharmaceuticallyacceptable salt, wherein R^(c) is alkyl.

[0058] (7) The 2-oxoquinoline compound of (3) or its pharmaceuticallyacceptable salt, wherein X′ is —(CH₂)_(p)—OC(═Y)—NR^(d)-(Alk^(b))_(s)-Ror —(CH₂)_(q)—NR⁸—C(=Z)-(NR^(f))_(w)-(Alk^(c))_(v)-R.

[0059] (8) The 2-oxoquinoline compound of (3) or its pharmaceuticallyacceptable salt, wherein W is —O—; R¹ is hydrogen atom or alkyl having1-3 carbons (the alkyl may be substituted or unsubstituted withalkylamino, amino, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl,acyloxy, acylthio, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl);and R² is —OR⁶ (where R⁶ represents hydrogen atom or alkyl having 1-3carbons (the alkyl may be substituted or unsubstituted with alkylamino,amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio,mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl)).

[0060] (9) The 2-oxoquinoline compound of any one of (3)-(8) or itspharmaceutically acceptable salt, wherein R is aryl, heteroaryl or

[0061] where aryl, heteroaryl, and each symbol in the formula are asdefined above.

[0062] (10) The 2-oxoquinoline compound of any one of (3)-(8) or itspharmaceutically acceptable salt, wherein R is

[0063] where each symbol is as defined above.

[0064] (11) The 2-oxoquinoline compound of any one of (3)-(10) or itspharmaceutically acceptable salt, wherein W is —O— and R² is —OR⁶ (whereR⁶ is a hydrogen atom or alkyl).

[0065] (12) The 2-oxoquinoline compound of any one of (3)-(11) or itspharmaceutically acceptable salt, wherein the substitution position ofWR¹ is position-j of the benzene ring, and the substitution position ofR² is position-i of the benzene ring.

[0066] (13) The 2-oxoquinoline compound of any one of (3)-(6) and(8)-(12) or its pharmaceutically acceptable salt, wherein Alk^(a) isalkylene and r=1.

[0067] (14) The 2-oxoquinoline compound of (3) or its pharmaceuticallyacceptable salt, wherein the 2-oxoquinoline compound excludes7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3carboxylic acid(2-pyridine-4-ylethyl)amide;7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-aminobenzyl)amide;7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-aminophenyl)ethyl]amide; and7-methoxy-2-oxo-8-pentyloxy-l,2-dihydroquinoline-3-carboxylic acid(4-aminophenyl)amide.

[0068] (15) The 2-oxoquinoline compound of (3) or its pharmaceuticallyacceptable salt, wherein the 2-oxoquinoline compound excludes compoundsin which W is —O—; R¹ is alkyl; R² is —OR⁶ (where R⁶ is alkyl); R^(a) ishydrogen; and X′ is —CONR^(c)-(Alk^(a))_(r)-R (where R^(c) is a hydrogenatom; Alk^(a) is methylene, ethylene or trimethylene; r is 0 or 1; and Ris aryl or heteroaryl).

[0069] (16) The 2-oxoquinoline compound of (5) or its pharmaceuticallyacceptable salt, wherein R is aryl (the aryl may be substituted orunsustituted with hydroxy, alkoxy, alkenyloxy, acyloxy, halogen atom,aralkyloxy, or glucuronic acid residue).

[0070] (17) The 2-oxoquinoline compound of (3) or its pharmaceuticallyacceptable salt, wherein R is aryl except phenyl or is heteroaryl exceptpyridyl.

[0071] (18) The 2-oxoquinoline compound of any one of (3)-(17) or itspharmaceutically acceptable salt, wherein the 2-oxoquinoline compound isselected from the group consisting of7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide (Example 3-1);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-aminobenzyl)amide (Example 3-2);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-aminophenyl)ethyl]amide (Example 3-3);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-aminophenyl)amide hydrochloride (Example 3-4);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl) amide (Example 3-5);8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide (Example 3-6);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-hydroxyphenyl)ethyl]amide (Example 3-7);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide (Example 3-B);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-pyridyl methyl)amide (Example 3-9);7-methoxy-2-oxo-S-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-piperidinoethyl)amide (Example 3-10);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-morpholinoethyl)amide (Example 3-11);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(3-pyridylmethyl)amide (Example 3-12);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-pyridylmethyl)amide (Example 3-13);3-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(2-phenylethyl)amide (Example 3-14);8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide (Example 3-15);8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide (Example 3-16);8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide hydrochloride (Example 3-17);8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide (Example 3-18);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(2-fluorophenyl)ethyl]amide (Example 3-19);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(3-fluorophenyl)ethyl]amide (Example 3-20);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-(4-hydroxy-3-methoxyphenyl)ethyl]amide (Example 3-21);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-chlorophenyl)ethyl]amide (Example 3-22);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-phenylethyl)amide (Example 3-23);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-methylbenzyl)amide (Example 3-24);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-fluorobenzyl)amide (Example 3-25);7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide (Example 3-26);7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl) ethyl]amide (Example 3-27);7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-hydroxyphenyl)ethyl]amide (Example 3-28),7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic aid(3,4-methylenedioxybenzyl)amide (Example 3-29);7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid(2-phenylethyl)amide (Example 3-30);7,8-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide (Example 3-31);7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide (Example 3-32);7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl)amide (Example 3-33);7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-morpholinoethyl) amide (Example 3-34);8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl) amide (Example 3-35);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid [2-(4-fluorophenyl)ethyl]amide (Example 3-36);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-pyridine-4-ylethyl)amide (Example 3-37);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-morpholinoethyl) amide (Example 3-38);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (4-pyridylmethyl) amide (Example 3-39);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (4-fluorobenzyl)amide (Example 3-40);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid [2-(4-hydroxyphenyl) ethyl]amide (Example 3-41);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl) amide (Example 3-42);1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-(4-fluorophenyl)ethyl]amide (Example 3-43);1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-morpholinoethyl)amide (Example 3-44);1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide (Example 3-45),7,8-dipentyloxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide (Example 3-46);8-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl)amide (Example 3-47);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(3,4-dihydroxybenzyl)amide (Example 3-48);7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-hydroxy-3-methoxybenzyl)amide (Example 3-49);1-O-(2-hydroxy-5-[(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-3-quinolyl)carbonylaminomethyl]phenyl)glucosidouronic acid and1-O-(2-hydroxy-4-[(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-3-quinolyl)carbonylaminomethyl]phenyl}glucosidouronic acid (Example 3-50);5-[7-methoxy-3-{(3,4-methylenedioxybenzyl)carbamoyl}-2-oxo-1,2-dihydro-8-quinolyloxy]pentanoicacid (Example 3-51);5-[7-methoxy-3-{(3-hydroxy-4-methoxybenzyl)carbamoyl}-2-oxo-1,2-dihydro-8-quinolyloxy]pentanoicacid (Example 3-52);8-(5-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide (Example 3-53);8-(5-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (4-hydroxy-3-methoxybenzyl)amide (Example 3-54);8-(4-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide (Example 3-55);7-methoxy-2-oxo-8-(4-oxopentyloxy)-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide (Example 3-56);8-(3-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide (Example 3-57);7-methoxy-2-oxo-8-(3-oxopentyloxy)-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide (Example 3-58);8-(2-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide (Example 3-59);7,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide (Example 4-1); 8-butoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (Example 5-1);8-ethoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (Example5-2); N-(4-fluorophenyl)carbamic acid(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)methyl ester(Example 6-1); N-pyridine-4-ylcarbamic acid(8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)methyl ester(Example 6-2); 3-dimethylaminomethyl-8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline (Example 7-1);8-butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (Example7-2); 8-ethoxy-7-methoxy-3-morpholinomethyl-2-oxo-1,2-dihydroquinoline(Example 7-3);N-[(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)methyl]-N′-(4-fluorophenyl)urea(Example 8-1) andN-[(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)methyl]-(4-hydroxyphenyl)acetamide(Example 8-2).

[0072] (19) A 2-oxoquinoline compound or its pharmaceutically acceptablesalt, the 2-oxoquinoline compound being selected from the groupconsisting of7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acidmethyl ester (Example 1-1);7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acidmethyl ester (Example 1-2);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester (Example 1-3); and1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester (Example 1-4),

[0073] (20) A 2-oxoquinoline compound or its pharmaceutically acceptablesalt, the 2-oxoquinoline compound being selected from the groupconsisting of7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(Example 2-1);8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (Example2-2); 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(Example 2-3);7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid(Example 2-4);7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(Example 2-5);1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (Example 2-6); and1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (Example 2-7).

[0074] (21)7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide (Example3-60) or its pharmaceutically acceptable salt.

[0075] (22) A pharmaceutical composition comprising, as an activeingredient, the 2-oxoquinoline compound of any one of (3)-(21) or itspharmaceutically acceptable salt.

[0076] (23) A cannabinoid receptor modulator comprising, as an activeingredient, the 2-oxoquinoline compound of any one of (3)-(21) or itspharmaceutically acceptable salt.

[0077] (24) A peripheral cannabinoid receptor modulator comprising, asan active ingredient, the 2-oxoquinoline compound of any one of (3)-(21)or its pharmaceutically acceptable salt, the 2-oxoquinoline compoundselectively acting on peripheral type cannabinoid receptors.

[0078] (25) The 2-oxoquinoline compound of any one of (3)-(21) or itspharmaceutically acceptable salt, wherein the 2-oxoquinoline compound isan immunomodulator, therapeutic agent for autoimmune diseases,antiallergic agent, or antiinflammatory agent.

[0079] (26) The 2-oxoquinoline compound of any of (3)-(21) or itspharmaceutically acceptable salt, wherein the 2-oxoquinoline compound isan antiinflammatory agent.

[0080] (27) An antiinflammatory agent comprising, as an activeingredient, the 2-oxoquinoline compound of (1) or (2) or itspharmaceutically acceptable salt.

[0081] Terminologies used herein are defined as follows:

[0082] The term “alkyl” means group having 1-10 carbon atoms, which maybe linear or branched, and specifically includes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl,neopentyl, t-pentyl, hexyl, isohexyl, neohexyl, heptyl, etc.

[0083] The group in R², R²′, R⁵, and R⁶ preferably contains 1-7 carbonatoms; more preferred in R⁶ is a linear alkyl containing 1-6 carbonatoms and still more preferred in R⁶ is methyl. Preferably, the group inR³ and R⁴ has 1-4 carbon atoms. The group in R¹, R⁷, R⁸ and R⁹ ispreferably a linear alkyl having 1-6 carbon atoms; more preferred isethyl, propyl, butyl or pentyl; still more preferred is propyl, butyl orpentyl; and particularly preferred is pentyl. The group in R¹⁰, R¹¹, R¹²and R¹³ preferably has 1-4 carbon atoms; preferred in R^(a), R^(b),R^(c), R^(d), R^(e), R^(e)′ and R^(f) is 1-4 carbon atoms; and morepreferred is methyl.

[0084] The term “alkenyl” means the linear or branched group having 2-10carbon atoms, and is specifically exemplified by vinyl, allyl, crotyl,2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, heptenyl, etc.

[0085] The group in R⁶, R⁷, R⁸ and R⁹ preferably contains 2-7 carbonatoms. Preferably R¹ contains 4-7 carbon atoms.

[0086] The term “alkynyl” means a linear or branched group having 2-10carbon atoms, and is specifically exemplified by ethynyl, propynyl,butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, hepynyl, etc.

[0087] The group in R⁶, R⁷, R⁸ and R⁹ preferably contains 2-7 carbonatoms. Preferably R¹ contains 4-7 carbon atoms.

[0088] The “alkylene” in Alk^(a), Alk^(b) and Alk^(c) means a linear orbranched chain having 1-4 carbon atoms, which is specificallyexemplified by methylene, ethylene, trimethylene, tetramethylene, etc.,and more preferred is methylene or ethylene. Particularly preferred ismethylene for Alk^(a); and particularly preferred is methylene for eachof Alk^(b) and Alk^(c).

[0089] The “alkenylene” in Alk^(a), Alk^(b) and Alk^(c) means a linearor branched chain having 2-4 carbon atoms, which is specificallyexemplified by vinylene, propenylene, butenylene, etc.

[0090] The term “alkoxy” means the group of which alkyl portioncorresponds to that having 1-4 carbon atoms among the above-definedalkyl groups, which is specifically exemplified by methoxy, ethoxy,propoxy, iospropyloxy, butyloxy, t-butyloxy, etc.

[0091] The term “cycloalkyl” means a saturated monocyclic alkyl having3-8 carbon atoms, which is specifically exemplified by cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0092] Preferably the group in R¹, R⁶, R⁷ and R⁸ contains 3-6 carbonatoms; preferably R contains 3-7 carbon atoms and particularly preferredis cyclohexyl.

[0093] The “cycloalkylalkyl” in R¹, R⁶, R⁷ and R⁸ means the group inwhich the cycloalkyl portion is the above-defined cycloalkyl containing3-6 carbon atoms and the alkyl portion is the above-defined alkylcontaining 1-4 carbon atoms. Specifically, the group is exemplified bycyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl,etc.

[0094] The “aryl” in R¹, R⁶, R⁷, R⁸ and R means an aromatic hydrocarbonhaving 6-16 carbon atoms and is specifically exemplified by phenyl,naphthyl, biphenyl, anthracenyl, indenyl, azulenyl, fluorenyl,phenanthrenyl, pyrenyl, etc.; preferred is phenyl or naphthyl; andparticularly preferred is phenyl.

[0095] The “arylalkyl” in R¹, R⁶, R⁷, R⁸, R¹² and R¹³ means the group inwhich the aryl portion corresponds to the above-defined aryl and thealkyl portion is the above-defined alkyl having 1-4 carbon atoms.Specifically, the group is exemplified by benzyl, phenethyl,phenylpropyl, phenylbutyl, naphthylmethyl, biphenylmethyl, etc.; andpreferred is benzyl.

[0096] The “heteroaryl” in R¹, R⁶, R⁷, R⁸ and R may be saturated orunsaturated with hydrogen atom and is specifically exemplified bypyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl,thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, tetrazolyl,thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl,pyrrolinyl, furyl, azepinyl, benzopyranyl, benzothienyl, benzotriazolyl,indolyl, isoindolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 1,8-naphthyridyl, 1,7-naphthyridyl, 1,6-naphthyridyl, 1,5-naphthyridyl, pyrido[2,3-d]pyrimidyl, thieno[2,3-b]pyridyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl,morpholyl, hydroazepinyl, hydroindolyl, hydroisoindolyl, hydroquinolyl,hydroisoquinolyl, etc; preferred is pyridyl, thienyl, piperidyl,piperidino, imidazolyl, or morpholyl; more preferred is pyridyl,piperidyl, or morpholyl; and particularly preferred is pyridyl.

[0097] The expression, R^(e) and R^(e)′ “together with the adjacentnitrogen atom, form a heteroaryl,” means a heteroaryl having one or morenitrogen atoms among above heteroaryl groups; specifically, the groupincludes pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl,morpholino, pyrazolyl, imidazolyl, tetrazolyl, triazolyl, pyrrolyl,pyrrolinyl, indolyl, hydroazepinyl, hydroindolyl, hydroisoindolyl,hydroquinolyl, hydroisoquinolyl, etc.; preferred is morpholino,piperidino or piperazinyl; and particularly preferred is morpholino.

[0098] The expression, R⁷ and R⁸, or R¹⁰ and R¹¹, “together with theadjacent nitrogen atom, form a heteroaryl” has the same meaning as theabove-defined expression, R^(e) and R^(e)′ “together with the adjacentnitrogen atom, form a heteroaryl.”

[0099] The “heteroarylalkyl” in R¹, R⁶, R⁷ and R^(a) means the group inwhich the heteroaryl portion is the same as the above-defined one andthe alkyl portion corresponds to the above-defined alkyl having 1-4carbon atoms; specifically, the group is exemplified by 2-thienylmethyl,3-furylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-isoquinolylmethyl,etc.; and preferred is 4-pyridylmethyl.

[0100] The “benzene-condensed cycloalkyl” in R means the group of whichcycloalkyl portion is the above-defined cycloalkyl; specifically, thegroup is exemplified by tetrahydronaphthalene, indan, etc.; andpreferred is tetrahydronaphthalene.

[0101] The “acyl” in R⁷ and R⁸ means a group in which carbonyl has beensubstituted with the above-defined alkyl or the above-defined aryl;specifically, the group is exemplified by formyl, acetyl, propionyl,butyryl, valeryl, benzoyl, naphthoyl, etc.

[0102] Further, each of substituted or unsustituted groups may besubstituted or unsustituted with one or more substituents, preferablywith 1 or 2 substituents Groups to be used as the substituents aredescribed below.

[0103] The term “halogen atom” means fluorine, chlorine, bromine andiodine; and preferred are fluorine and chlorine.

[0104] The terms “alkyl”, “alkoxy” and “acyl” indicate the same meaningsas the above-defined “alkyl”, “alkoxy” and “acyl,” respectively.

[0105] The “alkoxycarbonyl” means the group of which alkyl portion isthe above-defined alkyl having 1-4 carbon atoms; specifically, the groupis exemplified by methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, etc.; and preferred is ethoxycarbonyl.

[0106] The “alkylamino” means the group of which alkyl portioncorresponds to the above-defined alkyl having 1-4 carbon atoms;specifically, the group is exemplified by methylamino, ethylamino,propylamino, butylamino, dimethylamino, diethylamino, etc.

[0107] The “alkylthio” means the group of which alkyl portion is theabove-defined alkyl having 1-4 carbon atoms; specifically, the group isexemplified by methylthio, ethylthio, propylthio, butylthio, etc.

[0108] The “alkylsulfinyl” means the group of which alkyl portioncorresponds to the above-defined alkyl having 1-4,carbon atoms;specifically, the group is exemplified by methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, etc.

[0109] The “alkylsulfonyl” means the group of which alkyl portion is theabove-defined alkyl having 1-4 carbon atoms; specifically, the group isexemplified by methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl, etc.

[0110] The “alkenyloxy” means the group of which alkenyl portioncorresponds to the above-defined alkyl having 2-4 carbon atoms;specifically, the group is exemplified by ethenyloxy, propenyloxy,butenyloxy, etc.

[0111] The “acyloxy” means the group of which acyl portion is as definedabove and is specifically exemplified by formyloxy, acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, etc.; and preferred isacetyloxy.

[0112] The “acylthio” means the group of which acyl portion is asdefined above and is specifically exemplified by formylthio, acetylthio,propionylthio, butyrylthio, isobutyrylthio, etc.; and preferred isacetylthio.

[0113] The “acylamino” means the group of which acyl portion is asdefined above and is specifically exemplified by formylamino,acetylamino, propionylamino, butyrylamino, etc.; and preferred isacetylamino.

[0114] The “aralkyloxy” means the group of which aralkyl portion is theabove-defined arylalkyl; and the group is specifically exemplified bybenzyloxy, phenethyloxy, phenylpropyloxy, phenylbutyloxy,naphthylmethyloxy, biphenylmethyloxy, etc.

[0115] Preferred for R^(a) is hydrogen atom.

[0116] Substitution positions for the pair of WR¹ and R² are selectedfrom the group consisting of position-g, position-h, position-i andposition-j of 2-oxoquinoline but the respective substitution positionsare different from each other. Preferred combination of the substitutionpositions is the combination of positions-h and -i, or that ofpositions-i and -j on the ring of 2-oxoquinoline; particularly preferredis the combination of positions-i and -j. It is preferable that R² issubstituted at position-i.

[0117] Preferred for W is —O—, —S(O)_(t)— or —NR⁵—; more preferred is—O—. When W is —S(O)_(t)—, then t is preferred to be 0; when W is —NR⁵—,then it is preferable that R⁵ is a hydrogen atom

[0118] Preferred for R¹ is a hydrogen atom or alkyl; more preferred isalkyl; and particularly preferred is unsubstituted alkyl.

[0119] Preferred substituents of alkyl include alkylamino, amino,hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto,alkylthio, alkylsulfinyl and alkylsulfonyl; particularly preferred ishydroxy, carboxy or acyl. Alkyl, which has been substituted with any ofhydroxy, carboxy, and acyl, is preferred to have 5 carbon atoms intotal.

[0120] Specific examples of particularly preferred substituted alkylinclude 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl,5-hydroxypentyl, 2-oxopentyl, 3-oxopentyl, 4-oxopentyl, and4-carboxybutyl.

[0121] Preferred for R² are the respective groups except hydrogen atom;specifically, such groups are alkyl, —OR⁶, —NR⁷R⁸ and—(CH₂)_(u)′—S(O)_(u)R⁹ (where each symbol is as defined above); morepreferred are —OR⁶, —NR⁷R⁸ and —(CH₂)_(u)′—S(O)_(u)R₉; and particularlypreferred is —OR⁶.

[0122] When R² is —OR⁶, then preferred for R⁶ is hydrogen atom or alkyl;particularly preferred is alkyl. When R² is —NR⁷R⁸, then it ispreferable that one of R⁷ and R⁸ is hydrogen atom and the other isalkyl. When R² is —(CH₂)_(u)′—S(O)_(u)R⁹, preferred for u′ and u is 0,and preferred for R⁹ is alkyl.

[0123] Preferred for X are —COOR^(b), —CONR^(c)-(Alk^(a))_(f)-R,—(CH₂)_(p)—OC(═Y)—NR^(d)-(Alk^(b))_(s)-R,—(CH₂)_(q)—NR^(e)—C(=Z)-(NR^(f))_(w)-(Alk^(c))_(v)-R, —(CH₂)_(p)—OH and—

[0124] (where each symbol has the same meaning as defined above);particularly preferred is —COOR^(b) or —CONR^(c)(Alk^(a))_(r)-R; andmore preferred for X and X′ is —CONR^(c)-(Alk^(a))_(r)-R; in this case,preferred for R^(c) is hydrogen atom.

[0125] When X and X′ are —(CH₂)_(p)—OC(═Y)—NR^(d)-(Alk^(b))_(s)-R and—(CH₂)_(q)—NR^(e)—C(=Z)-(NR^(f))_(w)-(Alk^(c))_(v)-R, then preferred forY and Z is oxygen atom; preferred for p and q is 1; preferred for w is1; preferred for s and v is 0; and preferred for R^(e), R^(d) and R^(f)is hydrogen atom.

[0126] Preferred for R is aryl, heteroaryl or

[0127] (where each symbol has the same meaning as defined above); morepreferred is

[0128] In the above general formula, preferred for both A and B isoxygen atom and k is preferably 1.

[0129] Preferably, R is unsubstituted or has substituent of alkylsubstituted or unsubstituted with hydroxy or of hydroxy, alkoxy,alkenyloxy, acyl, acyloxy, halogen atom, nitro, amino, sulfonamide,alkylamino, aralkyloxy, pyridyl, piperidino, carboxy, alkoxycarbonyl,acylamino, aminocarbonyl, cyano or glucuronic acid residue; and when Rhas substituents, then the number of substituents is preferably 1 or 2.More preferred is alkyl that may be substituted or unsubstituted withhydroxy or is a hydroxy, alkoxy, halogen atom or glucuronic acidresidue; further preferred is alkyl that may be substituted orunsubstituted with hydroxy or is a hydroxy, alkoxy or halogen atom;particularly preferred is methyl group, hydroxy or methoxy. When R isphenyl group, substitution position(s) of the substituent(s) ispreferably located at the 4-position in the case of mono-substitution orthe 3-and 4-positions in the case of di-substitution.

[0130] Specifically, preferred for R is 4-methylphenyl, 4-hydroxyphenyl,3,4-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl,3-(6-carboxy-3,4,5-trihydroxy-2-pyranyloxy)-4-hydroxyphenyl or4-(6-carboxy-3,4,5-trihydroxy-2-pyranyloxy)-3-hydroxyphenyl; andparticularly preferred are 3,4-dihydroxy phenyl and4-hydroxy-3-methoxyphenyl.

[0131] The “pharmaceutically acceptable salt” specifically includes butis not limited to salts of alkaline metals such as sodium salts,potassium salts, cesium salts, etc; salts of alkaline earth metals suchas calcium salts, magnesium salts, and such; organic amine salts such astriethylamine salts, pyridine salts, picoline salts, ethanolamine salts,triethanolamine salts, dicyclohexylamine salts,N,N′-dibenzylethylenediamine salts, and such; salts of inorganic acidssuch as hydrochloride, hydrobromide, sulfate, phosphate, etc.; salts oforganic acids such as formate, acetate, trifluoroacetate, maleate,tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate, and such; salts of amino acids such as argininesalts, aspartates, glutamates, etc.

[0132] Diseases associated with the cannabinoid receptor includeautoimmune diseases (e.g., systemic lupus erythematosus, rheumatoidarthritis, ulcerative colitis, etc.) and inflammatory diseases (e.g.,acute and chronic pancreatites, etc.). Particularly, the inventivecompound can preferably be used to treat chronic pancreatitis that ishard to be treated with commonly used anti-inflammatory agents.

[0133] The “cannabinoid receptor modulator” means an agent capable ofregulating the biological activity of cannabinoid receptors, or an agentcapable of regulating the expression of cannabinoid receptors; theformer includes agonist, antagonist, inverse agonist, and agent capableof enhancing or reducing the sensitivity of cannabinoid receptors; andthe latter includes agents capable of enhancing or suppressing theexpression of cannabinoid receptors.

[0134] The present invention also includes a variety of isomers,prodrugs, metabolites, hydrates, and solvates of the respectivecompounds.

[0135] The term “prodrug” means derivatives of the inventive compoundshaving chemically or metabolically decomposable groups therein and thuscapable of being converted to the original compounds having the inherentdrug effects after administered into the living body, and which alsoincludes non-covalent complexes and salts thereof.

[0136] Compound [I] can be produced, for example, as follows, but themethod is not limited thereto.

[0137] In this formula, R¹² and R¹³ may be identical or different andrepresent hydrogen, alkyl, arylalkyl or cyano; other symbols have thesame meaning as defined above.

[0138] (Step 1)

[0139] Shown in this step is a method to obtain compound [3] bynitrating the ortho-position of formyl group on the benzene ring ofcompound [2].

[0140] It is possible to obtain a nitro compound by reacting compound[2] with fuming nitric acid in the presence of concentrated sulfuricacid in a solvent.

[0141] Such a solvent includes, for example, ether solvents such asdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such;halogen solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, and such; ester solvents such asethyl acetate, methyl acetate, butyl acetate, and such; alcohol solventssuch as methanol, ethanol, isopropyl alcohol, t-butanol, etc.; and acidsolvents such as acetic acid, acetic anhydride, and such; and preferredis acetic acid.

[0142] The reaction temperature is generally −50-200° C., and preferably−10-60° C. The reaction time is generally 15 minutes-48 hours,preferably 1-8 hours. The resulting nitro compound can further bereacted with an alkyl bromide such as bromopentane, etc. in the presenceof a base in an adequate solvent to give compound [3].

[0143] The suitable base includes, for example, sodium carbonate,potassium carbonate, lithium carbonate, sodium bicarbonate, potassiumbicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium hydride, n-butyllithium, s-butyllithium, t-butyllithium, andlithium diisopropylamide; and preferred is potassium carbonate.

[0144] The adequate solvent includes, for example, hydrocarbon solventssuch as benzene, toluene, xylene, hexane, etc.; ether solvents such asdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such;halogen solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, and such; ester solvents such asethyl acetate, methyl acetate, butyl acetate, and such; polar solventssuch as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone,etc.; alcohol solvents such as methanol, ethanol, isopropyl alcohol,t-butanol, and such; and preferred is dimethylformamide.

[0145] The reaction temperature is generally −10-200° C., preferably0-60° C. The reaction time is generally 15 minutes-48 hours, preferably1-8 hours.

[0146] (Step 2)

[0147] Compound [4] can be obtained by reducing the nitro group ofcompound [3] according to a commonly used method.

[0148] (Step 3)

[0149] Compounds [4] can be condensed with a malonic acid derivative [5]in the presence of an adequate acid or base to give compound [6]. Themalonic acid derivative includes, for example, diethyl malonate,dimethyl malonate, dibenzyl malonate, ethyl cyanoacetate, methylcyanoacetate, and such; and preferred is dimethyl malonate. The adequateacid includes, for example, benzoic acid, p-toluenesulfonic acid, aceticacid, methanesulfonic acid, hydrochloric acid, sulfuric acid, nitricacid, and such; benzoic acid is preferably used. The base includes, forexample, sodium hydride, potassium t-butoxide, sodium ethoxide, sodiummethoxide, ammonium acetate, sodium acetate, piperidine, pyridine,pyrrolidine, n-methylmorpholine, morpholine, triethylamine, and such;and preferred is piperidine.

[0150] The solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, xylene, hexane, heptane, etc.; ether solvents such asdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc; estersolvents such as ethyl acetate, methyl acetate, butyl acetate, etc.;polar solvents such as dimethylformamide, dimethylsulfoxide,acetonitrile, acetone, etc.; and alcohol solvents such as methanol,ethanol, isopropyl alcohol, t-butanol, etc.; and preferred is toluene.

[0151] The reaction temperature is generally 0-150° C., and preferably120° C. The reaction time is generally 2-48 hours, and preferably 24hours.

[0152] (Step 4)

[0153] Compound [6] can be hydrolyzed in the presence of an adequatebase in a solvent to give compound [7].

[0154] The solvent includes alcohol solvents such as methanol, ethanol,isopropyl alcohol, t-butanol, and such; water; or a mixed solventthereof.

[0155] The suitable base includes, for example, sodium carbonate,potassium carbonate, lithium carbonate, sodium bicarbonate, potassiumbicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium hydride, n-butyllithium, s-butyllithium, t-butyllithium, lithiumdiisopropylamide, and such; and preferred is lithium carbonate.

[0156] (Step 5)

[0157] Compound [7] that has been converted to an activated carboxylicacid derivative is allowed to react to compound [8] to yield compound[I] of interest.

[0158] The activated carboxylic acid derivative includes, for example,acid halide that can be obtained by treating carboxylic acid withthionyl chloride, phosphorus oxychloride, phosphorus pentachloride,oxalyl chloride, and such; active ester that can be obtained bycondensing carboxylic acid with 1-hydroxybenzotriazole,N-hydroxysuccinimide or the like by using a condensing agent such asdicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride, andsuch; mixed acid anhydride that can be obtained by reacting carboxylicacid to ethyl chlorocarbonate, pivaloyl chloride, isobutylchlorocarbonate or the like, and such; preferably used is active esterthat can be obtained from N-hydroxybenzotriazole by using EDChydrochloride as a condensing agent.

[0159] If required, it is also possible to use a base in combination inthe above reaction.

[0160] The base includes, for example, organic amines such astriethylamine, pyridine, and N-methylmorpholine; and preferred istriethylamine.

[0161] The solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane, xylene, and such; ether solvents such asdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such;halogen solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, and such; ester solvents such asethyl acetate, methyl acetate, butyl acetate, and such; polar solventssuch as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone,and such; and preferred is dimethylformamide.

[0162] The reaction temperature is generally 0-100° C., and preferably0-50° C. The reaction time is generally 15 minutes-24 hours, andpreferably 1-12 hours.

[0163] In this formula, R^(x) represents halogen atom; each of R¹′ andR⁶′ independently represents alkyl; and R^(b) is as defined above.

[0164] In this formula, R^(a)′ represents alkyl; R¹′, R⁶′, R^(x), R^(a)and R^(b) are as defined above.

[0165] In this formula, R¹″ represents alkyl; R¹′, R⁶′, R^(x), R^(a),R^(c), Alk^(a), R and r are as defined above.

[0166] (Step 1)

[0167] Compound [9] (3,4-dihydroxybenzaldehyde) is allowed to react byusing alkylating agent [10] in the presence of a base, therebyselectively alkylating the hydroxyl group located at the 4-position ofthe phenol of compound [9]. This results in the production of compound(11).

[0168] The alkylating agent to be used includes alkyl iodide such asmethyl iodide, etc.; alkyl bromide such as methyl bromide, ethylbromide, propyl bromide, butyl bromide, pentyl bromide, and such; alkylchloride such as pentyl chloride, and such; dialkyl sulfate such asdimethyl sulfate, and such; and preferably used is alkyl bromide.

[0169] The base includes, for example, sodium carbonate, potassiumcarbonate, lithium carbonate, cesium carbonate, calcium carbonate,sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium hydride, n-butyllithium,s-butyllithium, t-butyllithium, lithium diisopropylamide, and such; andpreferably used is lithium carbonate.

[0170] The solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, xylene, hexane, and such; ether solvents such asdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such;halogen solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane, and such; ester solvents such asethyl acetate, methyl acetate, butyl acetate, and such; polar solventssuch as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone,and such; alcohol solvents such as methanol, ethanol, isopropyl alcohol,t-butanol, and such; and preferably used is dimethylformamide.

[0171] The reaction temperature is generally −20-100° C., and preferably0-100° C. The reaction time is generally 15 minutes-48 hours, andpreferably 1-6 hours.

[0172] (Step 2)

[0173] Compound [11] can be reacted with fuming nitric acid in thepresence of concentrated sulfuric acid in a solvent, therebymono-nitrating the ortho-position of formyl group of compound [11] toobtain compound [12] (where compound [12] refers to compound [12a],compound [12b] and a mixture thereof).

[0174] The solvent includes, for example, ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc.; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, and such; ester solvents such as ethyl acetate,methyl acetate, butyl acetate, and such; alcohol solvents such asmethanol, ethanol, isopropyl alcohol, t-butanol, and such; acid solventssuch as acetic acid, acetic anhydride, and such; preferably used isacetic acid.

[0175] The reaction temperature is generally −50-200° C., and preferably−10-60° C.

[0176] Alternatively, compound [12] can be obtained by nitratingcompounds [11] by using lanthanum nitrate and sodium nitrate in thepresence of an acid in a solvent in this step.

[0177] The acid includes, for example, benzoic acid, p-toluenesulfonicacid, acetic acid, methanesulfonic acid, hydrochloric acid, sulfuricacid, nitric acid, and such; and preferred is hydrochloric acid.

[0178] The solvent includes, for example, the above-mentioned solventsand preferred is tetrahydrofuran.

[0179] The reaction temperature is generally −50-200° C., and preferably0-50° C.

[0180] (Step 3)

[0181] Compound [12] is allowed to react by using alkylating agent [13]in the presence of a base in a solvent, thereby alkylating the hydroxylgroup located in the phenol of compound [12]. This results in theproduction of compound [14] (which means regioisomers and a mixturethereof corresponding to compound [12]).

[0182] The alkylating agent to be used includes the alkylating agents asdescribed in Step 1 of Production method 2; and preferably used is alkylbromide.

[0183] The base includes the bases as described in Step 1 of Productionmethod 2; and preferably used is potassium carbonate.

[0184] The solvent includes the solvents as described in Step 1 ofProduction method 2; and preferably used is dimethylformamide.

[0185] The reaction temperature is generally −20-200° C., and preferably0-100° C. The reaction time is generally 15 minutes-48 hours, andpreferably 1-24 hr.

[0186] (Step 4)

[0187] Compound [14] is allowed to react to malonic acid in a solvent,thereby dehydration-condensing the formyl group moiety of compound [14].This results in the production of compound [15] (which meansregioisomers and a mixture thereof corresponding to compound [12]).

[0188] The solvent includes the solvents as described in Step 2 ofProduction method 2; and preferred is acetic acid.

[0189] The reaction temperature is generally −20-200° C., and preferably0-100° C. The reaction time is generally 2-72 hours, but preferred is3-24 hours.

[0190] (Step 5)

[0191] Compound [15] is esterified with alkylating agent [16] in thepresence of a base in a solvent, thereby protecting the carboxyl group.This reaction results in the production of compound [17] (which meansregioisomers and a mixture thereof corresponding to compound [15]).

[0192] The alkylating agent includes the alkylating agents as describedin Step 1 of Production method 2; and preferred is methyl iodide.

[0193] The base includes the bases as described in Step 1 of Productionmethod 2; and preferred is potassium carbonate.

[0194] The solvent includes the solvents as described in Step 1 ofProduction method 2; and preferred is dimethylformamide.

[0195] The reaction temperature is generally −20-200° C., and preferably0-50° C. The reaction time is generally 15 minutes-48 hours, andpreferably 1-24 hours.

[0196] (Step 6)

[0197] After the nitro group of compound [17] is reduced according to acommonly used method, the compound is condensed to construct theα-quinolone backbone. The reaction results in the production of compound[I-1a], compound [I-1a′], or a mixture thereof.

[0198] (Step 7)

[0199] Compound [I-1a], compound [I-1a′], or the mixture thereof, isalkylated by using alkylating agent [18] according to the same method asdescribed in Step 3 of Production method 2. The reaction alkylates theNH portion of the quinolone moiety and this results in the production ofthe corresponding compound [I-1b], compound [I-1b′] or a mixturethereof.

[0200] (Step 8)

[0201] The esterified moiety of compound [I-1a], compound [I-1a′],compound [I-1b] or compound [I-1b′] is hydrolyzed according to acommonly used method to obtain the corresponding compound [I-2a],compound [I-2a′], compound [I-2b] and compound [I-2b′] (these fourcompounds are combined to be compound [I-2]).

[0202] (Step 9)

[0203] Compound [I-2], which has been converted to an activatedcarboxylic acid derivative, can be treated and amide-condensed withcompound [8] in a solvent to give compound [I-3].

[0204] The activated carboxylic acid derivative includes, for example,acid halide that can be obtained by treating carboxylic acid withthionyl chloride, phosphorus oxychloride, phosphorus pentachloride,oxalyl chloride, and such; active ester that can be obtained bycondensing carboxylic acid with 1-hydroxybenzotriazole, N-hydroxysuccinimide or the like by using a condensing agent such asdicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride, and such; mixed acid anhydridethat can be obtained by reacting carboxylic acid with ethylchlorocarbonate, pivaloyl chloride, isobutyl chlorocarbonate or thelike; and preferably used is active ester obtained fromN-hydroxybenzotriazole by using EDC hydrochloride as a condensing agent.

[0205] If required, it is also possible to use a base in combination inthe above reaction. The base includes, for example, organic amines suchas triethylamine, pyridine, and N-methylmorpholine; and preferred istriethylamine.

[0206] The solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane, xylene, and such; ether solvents such asdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such;halogen solvents such as dichloromethane, chloroform, carbontetrachloxide, 1,2- dichloroethane, and such; ester solvents such asethyl acetate, methyl acetate, butyl acetate, and such; polar solventssuch as dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone,etc.; and preferred is dimethylformamide. The reaction temperature isgenerally 0-100° C., and preferably 0-50° C. The reaction time isgenerally 15 minutes-24 hours, and preferably 1-12 hours.

[0207] (Step 10)

[0208] Compound [I-3] is treated with a Lewis acid in a solvent, therebydealkylating the ether moiety. This reaction results in the productionof compound [I-4].

[0209] The Lewis acid includes, for example, titanic tetrachloride,aluminum chloride, aluminum bromide, trimethylsilyl iodide, borontrichloride, boron tribromide, and such; and preferred is borontribromide. Sulfur compound such as thiophenol, ethyl mercaptan, andsuch may be used in combination.

[0210] The solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane, xylene, and such; ether solvents such astetrahydrofuran, diglyme, and such; halogen solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,etc.; and preferred is dichloromethane.

[0211] The reaction temperature is generally −100-100° C., andpreferably −80-0° C. The reaction time is generally 15 minutes-24 hours,but preferred is 30 minutes-5 hours.

[0212] In this production method, it is also possible to obtain compound[I-3] by condensing compound [I-2a], [I-2a′] or a mixture thereof withcompound [8] in the same manner as described in Step 9 of Productionmethod 2 and then alkylating the NH portion of quinolone backbone in thesame manner as described in Step 7 of Production method 2.

[0213] Alternatively, it is also possible to obtain compound [I-3], forexample, by skipping Step 3, treating compound [12] by using theprocedure of Step 4 and later procedures for the ring formation of7-substituted 8-hydroxy-2-oxoquinoline, then carrying out the procedureof Step 9 for amide-condensation, followed by alkylation by the methodof Step 3. Thus, different combinations of the steps can be used for theproduction.

[0214] In this formula, each symbol is as described above.

[0215] (Step 1)

[0216] Compound [I-2], which is obtained by Production method 1 orProduction method 2, is treated with a reducing agent in a solvent,thereby reducing the carboxyl group of compound (I-2]. Compound [I-5] isobtained by the reaction in this step.

[0217] The reducing agent includes common reducing reagents for carboxylgroup, such as borane, etc., but it is preferable to use a method inwhich carboxylic acid is reduced after converted to an activatedcarbonyl derivative.

[0218] The activated carboxylic acid derivative includes, for example,mixed acid anhydride that can be obtained by reacting carboxylic acid toisopropyl chlorocarbonate, ethyl chlorocarbonate, pivaloyl chloride,isobutyl chlorocarbonate or the like; and preferred is an active esterobtained from isopropyl chlorocarbonate.

[0219] If required, it is also possible to use a base in combination inthe above reaction. The base includes, for example, organic amines suchas triethylamine, pyridine, and N-methylmorpholine; and preferred istriethylamine. Used for the reduction of activated carboxylic acid aresodium borohydride, lithium borohydride, and such; and preferred islithium borohydride.

[0220] The solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane, xylene, etc.; ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, and such; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, and such; and preferred is tetrahydrofuran.

[0221] In some cases in this reaction, base treatment should be carriedout after reduction. The base being used in this reaction includessodium hydroxide, potassium hydroxide, lithium hydroxide, potassiumcarbonate, sodium carbonate, and such; and preferred is sodiumhydroxide. The reaction temperature is generally −20-100° C., andpreferably −10-30° C. The reaction time is generally 15 minutes-24hours, and preferably 1-12 hours.

[0222] (Step 2)

[0223] Compound [I-5] is treated with isocyanate or thioisocyanatecompound [20] in the presence of a base in a solvent to give compound[I-6].

[0224] The isocyanate and thioisocyanate include, for example, aralkylisocyanate such as benzylisocyanate, and such; and arylisocyanate suchas phenyl isocyanate, 4-fluorophenyl isocyanate, pyridine-4-ylisocyanate, and such; and preferred is arylisocyanate.

[0225] The base includes, for example, organic amines such astriethylamine, pyridine, N-methylmorpholine, and such; and preferred istriethylamine.

[0226] The solvent includes the solvents as described in Step 1 ofProduction method 2; and preferred is chloroform.

[0227] The reaction temperature is generally −20-100° C., and preferably−10-30° C. The reaction time is generally 15 minutes-24 hours, andpreferably 1-12 hours.

[0228] (Step 3)

[0229] Compound [I-5] is treated with acid chloride and then with aminecompound [21] to give compound [I-7] in the presence of a base in asolvent.

[0230] The acid chloride includes methanesulfonyl chloride,p-toluenesulfonyl chloride, benzenesulfonyl chloride, and such; andpreferred is methanesulfonyl chloride.

[0231] The base includes, for example, organic amines such astriethylamine, pyridine, N-methylmorpholine, and such; and preferred istriethylamine.

[0232] The solvent includes the solvents as described in Step 1 ofProduction method 2; and preferred is tetrahydrofuran.

[0233] The reaction temperature is generally −20-100° C., and preferably−10-30° C. The reaction time is generally 15 minutes-24 hours, andpreferably 1-12 hours.

[0234] (Step 4)

[0235] When at least R^(e)′ is a hydrogen atom in compound [I-7],compound [I-7] can be subjected to a coupling reaction with isocyanateor thioisocyanate compound [22] in a solvent to give the correspondingcompound [I-8].

[0236] The isocyanate and thioisocyanate include those described in Step1 of Production method 3; and preferably used is arylisocyanate.

[0237] If required, it is also possible to use a base in combination inthe above reaction. The base includes, for example, organic amines suchas triethylamine, pyridine, and N-methylmorpholine; and preferred istriethylamine.

[0238] The solvent includes the solvents as described in Step 1 ofProduction method 2; and preferred is dimethylformamide.

[0239] The reaction temperature is generally 0-100° C., and preferably0-50° C. The reaction time is generally 15 minutes-24 hours, andpreferably 1-12 hours.

[0240] (Step 5)

[0241] When at least R^(e)′ is a hydrogen atom in compound [I-7],compound [I-7] can be subjected to a coupling reaction with an activatedcarboxylic acid derivative in a solvent to obtain compound [I-8′].

[0242] The carboxylic acid derivative to be used in the couplingreaction using an activated carboxylic acid derivative includes acidhalide, active ester, mixed acid anhydride, etc. obtained fromcarboxylic acid [23] by the procedure as described in Step 9 ofProduction method 2; and preferred is an active ester obtained fromN-hydroxybenzotriazole by using EDC hydrochloride as a condensing agent.

[0243] The solvent includes the solvents as described in Step 1 ofProduction method 2; and preferred is dimethylformamide.

[0244] The reaction temperature is generally 0-100° C., and preferably0-50° C. The reaction time is generally 15 minutes-24 hours, andpreferably is 1-12 hours.

[0245] Compound [I] produced in the above-mentioned manner can beseparated and purified, for example, by known methods such asconcentration, concentration under reduced pressure, extraction withsolvent, crystallization, re-crystallization, chromatography and thelike.

[0246] Further, pharmaceutically acceptable salts of compound [I] andalso various isomers of compound [I] can be produced according topreviously known methods.

[0247] Compound [I] and pharmaceutically acceptable salts thereofexhibit pharmaceutical effects on diseases known to be associated withcannabinoid receptors, particularly diseases associated with peripheralcell tissues (immune disease, various types of inflammation, allergicdiseases, etc.) in mammals.

[0248] In other words, compound [I] and pharmaceutically acceptablesales thereof selectively act on cannabinoid receptors, particularly onperipheral cannabinoid receptors, and thus have excellentimmunomodulating action, anti-inflammatory action and antiallergicaction, but exert fewer side effects on the central nervous system.

[0249] Thus, compound [I] and pharmaceutically acceptable salts thereofare useful as modulators for cannabinoid receptors (particularly forperipheral cannabinoid receptors), immunomodulators, therapeutic agentsfor autoimmune diseases, anti-inflammatory agents and antiallergicagents.

[0250] When the compound [I] or their pharmaceutically acceptable saltsare used as a pharmaceutical composition, they may be formulated intotablets, pills, powders, granules, suppositories, injections, eye drops,liquid, capsules, troaches, aerosols, elixirs, suspensions, emulsions,syrups, and so on by using a standard method, generally together withknown pharmacologically acceptable carriers, excipients, diluents,extenders, disintegrators, stabilizers, preservatives, buffers,emulsifiers, aromatizers, colorants, edulcorants, viscosity increasingagents, flavors, solubilizers, or other additives such as water; plantoil; alcohols such as ethanol or benzyl alcohol, polyethylene glycol,glycerol triacetate, gelatin, lactose; or carbohydrates such as starch,magnesium stearate, talc, lanolin, vaseline, etc. The composition may beadministered orally or parenterally.

[0251] The dose depends on the type and condition of disease, the typeof compound to be administered and administration route, age, sex, andbody weight of patient, etc. In general, compound [I] is daily given toan adult at a dose of 0.1-1000 mg, and preferably 1-300 mg, once ordivided in the case of oral administration.

[0252] Further, the compounds of the present invention can be used asanimal drugs.

BEST MODE FOR CARRYING OUT THE INVENTION

[0253] The present invention is illustrated more specifically byreferring to the following Examples. However, the present invention isnot limited thereto.

Reference Example 1

[0254] 4-Methoxy-2-nitro-3-pentyloxybenzaldehyde

[0255] Isovanillin (200 g), acetic acid (700 ml), and concentratedsulfuric acid (0.2 ml) were mixed and the resultant suspension wascooled to 0° C., to which a solution of fuming nitric acid (57.2 ml) inacetic acid (200 ml) was added dropwise over a period of 30 minutes. Themixture was stirred for 40 minutes, and then water (400 ml) was addedthereto and the crystals were collected through filtration to give amixture of 3-hydroxy-4-methoxy-2-nitrobenzaldehyde and3-hydroxy-4-methoxy-6-nitrobenzaldehyde (56.4 g).

[0256] The resultant mixture was mixed with dimethylformamide (700 ml) ,and potassium carbonate (136.7 g) and bromopentane (127.7 ml) weresuccessively added to this solution. After being stirred at 100° C. for4 hours, the reaction solution was filtered, and was separated with theaddition of water (600 ml) and a mixture of hexane and ethyl acetate ata ratio of 1:1 (600 ml) The aqueous layer was extracted with a mixtureof hexane and ethyl acetate at a ratio of 1:1 (600 ml), and the combinedorganic layer was dried over anhydrous magnesium sulfate, filtered toremove the desiccating agent, and concentrated under reduced pressure.The resultant crystals were collected through filtration. The filtratewas concentrated, and the resultant crystals were collected throughfiltration. This was repeated again, and the filtrate was concentratedto give 4-methoxy-2-nitro-3-pentyloxybenzaldehyde as a red oilysubstance (117 g). The filtered crystals were combined to give4-methoxy-6-nitro-3-pentyloxybenzaldehyde as yellow crystals (90.1 g)(Table 1).

Reference Example 2

[0257] 2-Amino-4-methoxy-3-pentyloxybenzaldehyde

[0258] 4-Methoxy-2-nitro-3-pentyloxybenzaldehyde (2.213 g) obtained inReference Example 1 was dissolved in ethanol (22 ml), and tin chloridedihydrate (9.34 g) was added thereto. After being heat-refluxed for 4hours, the reaction solution was cooled with ice, and a saturatedaqueous solution of sodium hydrogencarbonate was added to the solutionto render it alkaline. Then the solution was extracted with ethylacetate (50 ml), and the organic layer was dried over anhydrous sodiumsulfate, filtered to remove the desiccating agent, and concentratedunder reduced pressure. The resultant residue was purified throughsilica-gel column chromatography (eluent: a mixture of n-hexane andethyl acetate at a ratio of 5;1) to obtain2-amino-4-methoxy-3-pentyloxybenzaldehyde (1.675 g) (Table 1).

Reference Example 3

[0259] 3-Hydroxy-4-methoxybenzaldehyde

[0260] 3,4-Dihydroxybenzaldehyde (2.76 g, 20 mmol) was dissolved in DMF(15 ml), and methyl iodide (37.4 ml, 60 mmol) and anhydrous lithiumcarbonate (4.4 g, 60 mmol) were successively added to this solution.After being stirred at an external temperature of 90° C. for 1.5 hours,the reaction mixture was cooled to room temperature and the inorganicsalt was filtered off. A saturated aqueous solution of ammonium chloride(200 ml) was added to the filtrate to adjust the aqueous layer to a pHof from 7 to 8, and the solution was extracted with ethyl acetate (300ml×2). The combined organic layer was washed with a saturated aqueoussolution of sodium chloride (300 ml), dried over anhydrous magnesiumsulfate, filtered to remove the desiccating agent, and concentratedunder reduced pressure to give the title compound (2.5 g, 82.2%) (Table1).

Reference Example 4

[0261] 3-Hydroxy-4-methoxy-2-nitrobenzaldehyde (4a)

[0262] 3-Hydroxy-4-methoxy-6-nitrobenzaldehyde (4b)

[0263] 3-Hydroxy-4-methoxybenzaldehyde (15.2 g, 0.1 mol) obtained in thesame manner as in Reference Example 3 was dissolved in THF (150 ml), towhich sodium nitrate (8.5 g, 0.1 mol) and lanthanum nitrate hexahydrate(8.7 g, 0.2 mol) were added, and then a mixture of concentratedhydrochloric acid and water at a ratio of 1:1 (70 ml) was added dropwiseover a period of 20 minutes. The mixture was stirred for 40 minutes atroom temperature, and the separated organic layer was successivelywashed with water (50 ml), a saturated aqueous solution of sodiumhydrogencarbonate (50 ml), and a saturated aqueous solution of sodiumchloride (100 ml), dried over anhydrous magnesium sulfate, filtered toremove the desiccating agent, and concentrated under reduced pressure togive a mixture of the title compounds 4a and 4b as pale red crystals(4a:4b=1:1, 13.3 g, yield 67.5%) (Table 2).

Reference Example 5

[0264] 4-Methoxy-2-nitro-3-pentyloxybenzaldehyde (5a)

[0265] 4-Methoxy-6-nitro-3-pentyloxybenzaldehyde (5b)

[0266] The mixture of 3-hydroxy-4-methoxy-2-nitrobenzaldehyde (4a) and3-hydroxy-4-methoxy-6-nitrobenzaldehyde (4b) (4a:4b=1:1, 12.3 g, 62.4mmol) obtained in Reference Example 4 was dissolved in DMF (20 ml), andbromopentane (11.3 g, 74.9 mmol) and anhydrous potassium carbonate (12.9g, 93.6 mmol) were successively added to this solution. After beingstirred at an external temperature of 90° C. for 1.5 hours, the reactionmixture was cooled to room temperature and the inorganic salt wasfiltered off. A saturated aqueous solution of ammonium chloride (200 ml)was added to the filtrate to adjust the aqueous layer to a pH of from 7to 8, and the solution was extracted with ethyl acetate (300 ml×2). Thecombined organic layer was washed with a saturated aqueoussolution ofsodium chloride (300 ml), dried over anhydrous magnesium sulfate,filtered to remove the desiccating agent, and concentrated under reducedpressure to give a crude mixture of the title compounds 5a and 5b (5a:5b=1:1, 17.12 g, quant.) (Tables 2 and 3). This crude product was usedimmediately in the subsequent reaction.

Reference Example 6

[0267] 2-(4-Methoxy-2-nitro-3-pentyloxybenzylidene)malonic acid (6a)

[0268] 2-(4-Methoxy-2-nitro-5-pentyloxybenzylidene)malonic acid (6b)

[0269] The crude product of 4-methoxy-2-nitro-3-pentyloxy-benzaldehyde(5a) and 4-methoxy-6-nitro-3-pentyloxybenzaldehyde (5b) (5a:5b=1:1,17.12 g, 64.1 mmol) obtained in Reference Example 5 was dissolved inacetic acid (190 ml), to which malonic acid (20 g, 192 mmol) was added,and the mixture was stirred at an external temperature of 60° C. for 16hours. After toluene (100 ml×2) was added to the reaction solution toremove acetic acid by azeotropic distillation, an aqueous solution ofsodium hydroxide was added to the residue to adjust the aqueous solutionto a pH of from 7 to 8, and the solution was washed with ethyl acetate(200 ml×2). The aqueous layer was acidified (pH=1 to 2) withconcentrated hydrochloric acid, and was extracted with ethyl acetate(300 ml×2). The combined organic layer was washed with a saturatedaqueous solution of sodium chloride (300 ml), dried over anhydrousmagnesium sulfate, filtered to remove the desiccating agent, andconcentrated under reduced pressure to give a crude mixture of the titlecompounds 6a and 6b (6a:6b=1:1, 23.3 g, overweight) (Table 3). Thiscrude product was used immediately in the subsequent reaction.

Reference Example 7

[0270] Dimethyl 2-(4-methoxy-2-nitro-3-pentyloxybenzylidene)malonate(7a)

[0271] Dimethyl 2-(4-methoxy-2-nitro-5-pentyloxybenzylidene)malonate(7b)

[0272] The crude product of2-(4-methoxy-2-nitro-3-pentyloxy-benzylidene)malonic acid (6a) and2-(4-methoxy-2-nitro-5-pentyloxy-benzylidene)malonic acid (6b)(6a:6b=1:1, 23.4 g, 64.1 mmol) obtained in Reference Example 6 wasdissolved in DMF (160 ml), and methyl iodide (17.6 ml, 282 mmol) andanhydrous potassium carbonate (26.6 g, 192 mmol) were added to thissolution The mixture was stirred at room temperature for 1.5 hours, towhich a saturated aqueous solution of ammonium chloride (800 ml) wasadded, and the solution was washed with ethyl acetate (300 ml×2). Thecombined organic layer was successively washed with water (300 ml) and asaturated aqueous solution of sodium chloride (300 ml), dried overanhydrous magnesium sulfate, filtered to remove the desiccating agent,and concentrated under reduced pressure to give a crude mixture of thetitle compounds 7a and 7b (7a:7b=1:1, 23.2 g, 94.8%) (Table 4). Thiscrude product was used immediately in the subsequent reaction.

Reference Example 8

[0273] 1-Methyl-4-bromo-1-t-butyldimethylsilyl ether Step 1

[0274] 2-Methyltetrahydrofuran (5.07 g, 41.7 mmol) was dissolved intrichloromethane (36 ml), and tetraethylammonium bromide (9.2 g, 43.8mmol) was added thereto. Trifluoroborane etherate (5.56 ml, 43.8 mmol)was added dropwise to this solution at room temperature over a period of10 minutes. After being stirred at room temperature for 16 hours, thereaction solution was cooled with ice, and a saturated aqueous solutionof sodium hydrogencarbonate (40 ml) was added thereto to separate theorganic layer. The aqueous layer was further extracted withtrichloromethane (40 ml), and the combined organic layer wassuccessively washed with water (40 ml) and a saturated aqueous solutionof sodium chloride (40 ml), dried over anhydrous sodium sulfate,filtered to remove the desiccating agent, and concentrated under reducedpressure to give 1-methyl-4-bromo-1-butanol (5.07 g, 72.8%) as a paleyellow oily substance. This product was used immediately in thesubsequent reaction.

[0275] DMSO-d6, 400 MHz; 4.4(bs, 1H), 3.5-3.7(m, 1H), 3.53(t, 2H, J=6.8Hz), 1.8-1.9(m, 2H), 1.3-1.5(m, 2H), 1.04(d, 3H, J=6.2 Hz). Step 2

[0276] 1-Methyl-4-bromo-1-butanol (5.07 g, 30.4 mmol) obtained in Step 1was dissolved in dichloromethane (25 ml), and t-butyldimethylsilylchloride (9.64 g, 36.5 mmol) and imidazole (4.89 g, 45.6 mmol) weresuccessively added thereto while being cooled with ice. After beingstirred at room temperature for 7 hours, the reaction solution wascooled again with ice, and a saturated aqueous solution of sodiumhydrogencarbonate (50 ml) was added thereto to separate the organiclayer. The organic layer was successively washed with water (50 ml) anda saturated aqueous solution of sodium chloride (50 ml), dried overanhydrous sodium sulfate, filtered to remove the desiccating agent, andconcentrated under reduced pressure. The residue was purified throughsilica-gel column chromatography (eluent: a mixture of hexane and ethylacetate at a ratio of 100:1) to obtain the title compound (6.35 g,74.3%).

[0277] DMSO-d6,400 MHz: 3.8-3.9(m, 1H), 3.3-3.5(m, 2H), 1.8-2.0(m, 2H),1.5-1.6(m, 2H), 1.13(d, 3H, J=6.1 Hz), 0.87(s, 9H), 0.04(s, 6H).

EXAMPLE 1-1

[0278] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester

[0279] 2-Amino-4-methoxy-3-pentyloxybenzaldehyde (1.675 g) obtained inReference Example 2 was dissolved in toluene (16 ml), to which dimethylmalonate (2.40 ml), piperidine (1.04 ml), and benzoic acid (80 ml) wereadded, and the mixture was stirred at an external temperature of 120° C.for 27 hours. After the reaction solution was cooled to roomtemperature, a saturated aqueous solution of sodium hydrogencarbonate(1600 ml) was added thereto to separate the organic layer, and theaqueous layer was extracted with toluene (30 ml). The combined organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous sodium sulfate, filtered to remove the desiccatingagent, and concentrated under reduced pressure. The residue was purifiedthrough silica-gel chromatography (eluent: a mixture of chloroform andethyl acetate at a ratio of 1:1) to obtain the title compound (251 mg)(Table 5).

EXAMPLE 1-2 (Simultaneous synthesis with Example 1-1)

[0280] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester (Example 1-1)

[0281] 7-Methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester (Example 1-2)

[0282] The crude product of dimethyl2-[(4-methoxy-2-nitro-3-pentyl-oxyphenyl) methylene]propane-1,3-dioate(7a) and dimethyl2-[(4-methoxy-2-nitro-5-pentyloxyphenyl)methylene]propane-1,3-dioate(7b) (7a:7b=1:1, 23.1 g, 60.6 mmol) obtained in Reference Example 7 wasdissolved in acetic acid (260 ml) and water (17 ml), and the solutionwas heated at an external temperature of 60° C. To this reactionsolution, reduced iron (27.1 g, 48.5 mmol) was gradually added withattention to effervescence, and the mixture was further stirred at anexternal temperature of 90° C. for 1.5 hours. After filtration, water(500 ml) was added to the filtrate, and the solution was extracted withethyl acetate (300 ml×2). The combined organic layer was successivelywashed with a 1% hydrochloric acid aqueous solution (500 ml) and asaturated aqueous solution of sodium chloride (300 ml), dried overanhydrous magnesium sulfate, filtered to remove the desiccating agent,and concentrated under reduced pressure. The residue was purifiedthrough column chromatography (eluent: a mixture of n-hexane and ethylacetate at a ratio of 1:1) to obtain the title compounds of Example 1-1(8.56 g, 44.2%) and Example 1-2 (4.83 g, 25.0%) as pale yellow crystals(Table 5). A crude product of 7a and 7b (7a:7b=1:1, 23.2 g, 94.8%) wasalso obtained.

EXAMPLE 1-3

[0283]1-Methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester

[0284] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester (1.02 g, 3.2 mmol) obtained in the same manner as inExample 1-1 was dissolved in DMF (10 ml), and methyl iodide (0.4 ml, 6.4mmol) and anhydrous potassium carbonate (0.89 g, 6.4 mmol) were added tothis solution. After the mixture was stirred at an external temperatureof 60° C. for 1.5 hours, a saturated aqueous solution of ammoniumchloride (80 ml) was added thereto to adjust the solution to a pH of 8,and the solution was washed with ethyl acetate (50 ml×2). The combinedorganic layer was successively washed with a saturated aqueous solutionof sodium chloride (50 ml), dried over anhydrous magnesium sulfate,filtered to remove the desiccating agent, and concentrated under reducedpressure. The residue was purified through silica-gel chromatography(eluent: a mixture of chloroform and ethyl acetate at a ratio of 10:1)to obtain the title compound (532 mg, 49.91) (Table 5).

[0285] A compound shown in Example 1-4 was obtained in the same manneras in Reference Examples and Example 1-3 above. Chemical structure andproperties of the compound are shown in Table 6.

EXAMPLE 2-1

[0286] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid

[0287] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester (240 mg) obtained in Example 1-1 was dissolved inmethanol (7 ml) and water (3 ml), to which sodium hydroxide (120 ml) wasadded, and the solution was stirred at room temperature for 1.5 hours.While the reaction vessel was cooled with ice, the solution wasacidified with the addition of concentrated hydrochloric acid, andextracted with ethyl acetate (20 ml). The organic layer was dried overanhydrous sodium sulfate, filtered to remove the desiccating agent, andconcentrated under reduced pressure to give the title compound (228 ml)(Table 6).

[0288] Compounds shown in Examples 2-2 to 2-7 were obtained in the samemanner as in Reference Examples and Example 2-1 above. Chemicalstructures and properties of the compounds are shown in Tables 6 to 8.

EXAMPLE 3-1

[0289] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-pyridine-4-ylethyl)amide

[0290] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (30.0 mg) obtained in Example 2-1, 2-pyridine-4-ylethylamine (36.0mg), and 1-hydroxybenzotriazole hydrate (17.3 mg) were dissolved indimethylformamide (2 ml), and1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (24.5 mg)was successively added to this solution while being cooled with ice.After the reaction solution was stirred at room temperature for 5 hours,ethyl acetate (3 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (3 ml) were added to this solution. The organic layerwas separated and dried over anhydrous sodium sulfate, filtered toremove the desiccating agent, and concentrated under reduced pressure.The resultant residue was purified through column chromatography(eluent: a mixture of chloroform and methanol at a ratio of 25:1) toobtain the title compound (35 mg) as colorless crystals (Table 8).

[0291] Compounds shown in Examples 3-2 to 3-4 were obtained in the samemanner as in Example 3-1 above. Chemical structures and properties ofthe compounds are shown in Table 9.

EXAMPLE 3-5

[0292] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide

[0293] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (50 mg, 0.164 mmol) obtained in the same manner as in Example 2-1was dissolved in dichloromethane (1 ml), and DMF (cat.) was addedthereto, followed by thionyl chloride (0.018 ml, 0.24 mmol), and thenthe solution was stirred at room temperature for 1.0 hour. Toluene (4ml×2) was added to the reaction solution to remove the excess acid andthionyl chloride by evaporation, and an acid chloride was obtained aspale yellow crystals. The crystals were dissolved in dichloromethane (1ml). and the solution was added dropwise to a solution of3,4-methylenedioxybenzylamine (0.08 ml, 0.655 mmol) in dichloromethane(1 ml) prepared separately, and then the reaction solution was stirredat room temperature for 2 hours. The reaction solution was concentrated,and the residue was purified through column chromatography (eluent; amixture of chloroform and ethyl acetate at a ratio of 10:1) to obtainthe title compound (47 mg, 65.4%) (Table 10).

[0294] Compounds shown in Examples 3-6 to 3-54, and 3-60 were obtainedin the same manner as in Reference Examples and Examples 3-1 and 3-5above. Chemical structures and properties of the compounds are shown inTables 10 to 26, and 28.

EXAMPLE 3-55

[0295]8-(4-Hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide

[0296] In the usual manner, 8-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide (503 mg;Example 3-47) was alkylated with1-methyl-4-bromo-1-t-butyl-dimethylsilyl ether obtained in ReferenceExample 8, and then t-butyldimethylsilyl group was removed to give thetitle compound (493 mg) (Table 26).

[0297] Compounds shown in Examples 3-56 to 3-59 were obtained in thesame manner as in Example 3-55 above. Chemical structures and propertiesof the compounds are shown in Tables 27 and 28.

EXAMPLE 4-1

[0298] 7,8-Dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide

[0299] 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-(4-fluorophenyl)ethyl]amide (340 mg, 0.80 mmol) obtained in thesame manner as in Example 3-5 was dissolved in dichloromethane (4 ml),and boron tribromide (1.0 M solution in dichloromethane; 2.4 ml, 2.4mmol) was added dropwise thereto at an internal temperature of −60° C.under a nitrogen stream. The solution was allowed to warm to roomtemperature, and was stirred for 0.5 hour. The reaction solution waspoured into ice water (40 ml) to precipitate crystals. These crystalswere collected through filtration, washed with water (10 ml), and driedunder reduced pressure to give the title compound (247.5 mg, 90.7%)(Table 29).

EXAMPLE 5-1

[0300] 8-Butoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquionoline

[0301] 8-Butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(1.46 g, 5.00 mmol) obtained in the same manner as in Example 2-1 wasdissolved in THF (20 ml), and triethylamine (1,53 ml, 11.0 mmol) andisopropyl chlorocarbonate (1.35 g, 11.0 mmol) were successively addedthereto while being cooled with ice. After the solution was stirred atthe same temperature for 15 minutes, an aqueous solution of sodiumborohydride (2.08 g, 55.0 mmol, 20 ml) was added thereto while beingcooled with ice, and the solution was further stirred at the sametemperature for 1 hour. A 50% sodium hydroxide aqueous solution (20 ml)was added to the solution, which was then stirred at room temperaturefor 1 hour, and water (50 ml) and chloroform (50 ml) were added theretoto separate the organic layer. The aqueous layer was further extractedwith chloroform (30 ml), and the combined organic layer was dried overmagnesium sulfate, filtered to remove the desiccating agent, andconcentrated under reduced pressure. The resultant residue was purifiedthrough column chromatography (eluent: a mixture of hexane and ethylacetate at a ratio of 1:3) to obtain the title compound (1.28 g, yield92%) as colorless crystals (Table 29).

[0302] A compound shown in Example 5-2 was obtained in the same manneras in Example 5-1 above. Chemical structure and properties of thecompound are shown in Table 29.

EXAMPLE 6-1

[0303] N-(4-Fluorophenyl)carbamic acid (8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl ester

[0304] 8-Butoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquionoline(100 mg, 0.361 mmol) obtained in the same manner as in Example 5-1 wasdissolved in chloroform (1 ml) , and triethylamine (10 μl) and4-fluorophenyl isocyanate (45 μl, 0.396 mmol) were successively addedthereto while being cooled with ice. The mixture was stirred at the sametemperature for 5 hours, to which methanol (100 μl) was added, andconcentrated under reduced pressure. The resultant residue was dissolvedin THF, silica gel was slurried with the resultant solution, and thesolution was purified through column chromatography (eluent: a mixtureof hexane and ethyl acetate at a ratio of 1:3) to obtain the titlecompound (128 mg, yield 86%) as colorless crystals (Table 30).

EXAMPLE 6-2

[0305] N-Pyridine-4-ylcarbamic acid(8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl ester

[0306] 8-Ethoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquionoline(100 mg, 0.4 mmol) obtained in the same manner as in Example 5-1 wassuspended in methylene chloride (1.5 ml), and pyridine (39 μl, 0.48mmol) and 4-nitrophenylchloroformate (97 mg, 0.48 mmol) were addedthereto while being cooled with ice. The mixture was stirred at the sametemperature for 1 hour. After completion of the reaction,dimethylformamide (1.5 ml) was added, and then triethylamine (280 μl,2.0 mmol) and 4-aminopyridine (188 mg, 2.0 mmol) were added to thereaction mixture while being cooled with ice, and the mixture wasstirred at room temperature for 15 hours. After completion of thereaction, chloroform (15 ml) and a saturated aqueous solution of sodiumbicarbonate (15 ml) were added to the mixture for separation. Theorganic layer was dried over anhydrous sodium sulfate, filtered toremove the desiccating agent, and concentrated. The resultant residuewas purified through preparative thin layer chromatography (developingeluent: a mixture of chloroform and methanol at a ratio of 90:10) toobtain the title compound (56 mg, yield 38%) as pale yellow crystals(Table 30).

EXAMPLE 7-1

[0307]3-Dimethylaminomethyl-8-ethoxy-7-methoxy2-oxo-1,2-dihydro-quinoline

[0308] 8-Ethoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline(200 mg, 0.80 mmol) obtained in the same manner as in Example 5-1 wasdissolved in THF (5 ml), and triethylamine (134 μl, 0.96 mmol) andmethanesulfonyl chloride (68 μl, 0.88 mmol) were successively addedthereto while being cooled with ice. The mixture was stirred at the sametemperature for 30 minutes, to which 40% aqueous solution ofdimethylamine (7.0 ml) was added at a time, and was further stirred atroom temperature for one hour. Water (20 ml) and chloroform (20 ml) wereadded to the reaction solution, and the organic layer was separated. Theaqueous layer was further extracted with chloroform (10 ml), and thecombined organic layer was concentrated. The resultant residue wasdissolved in 1 N hydrochloric acid (5 ml), and the solution was washedthree times with ethyl acetate (5 ml×3). The aqueous layer wasneutralized with a saturated aqueous solution of sodium bicarbonate, andwas extracted two times with chloroform (5 ml×2). The combined organiclayer was dried over magnesium sulfate and concentrated under reducedpressure, and the resultant residue was washed with hexane to give thetitle compound (128 mg, yield 58%) as colorless crystals (Table 30).

EXAMPLE 7-2

[0309] 8-Butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline

[0310] 8-Butoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline(431 mg, 1.55 mmol) obtained in the same manner as in Example 5-1 wasdissolved in THF (10 ml), and triethylamine (260 μl, 1.87 mmol) andmethanesulfonyl chloride (132 μl, 1.71 mmol) were successively addedthereto while being cooled with ice. The mixture was stirred at the sametemperature for 20 minutes, to which 28% aqueous ammonia (20 ml) wasadded at a time, and was further stirred at room temperature for 1 hour.Water (20 ml) and chloroform (20 ml) were added to the reactionsolution, and the organic layer was separated. The aqueous layer wasfurther extracted with chloroform (10 ml), and the combined organiclayer was dried over magnesium sulfate, filtered to remove thedesiccating agent, and concentrated under reduced pressure. Theresultant residue was purified through column chromatography (eluent: amixture of chloroform, methanol and aqueous ammonia at a ratio of90:10:1) to obtain the title compound (146 mg, 34%) as colorlesscrystals (Table 31).

[0311] A compound shown in Example 7-3 was obtained in the same manneras in Example 7-1 or 7-2 above. Chemical structure and properties of thecompound are shown in Table 31.

EXAMPLE 8-1

[0312]N-[(8-Butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)-methyl]-N′-(4-fluorophenyl)urea

[0313] 8-Butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (56.6mg, 0.205 mmol) obtained in Example 7-2 was dissolved in chloroform (1ml), and 4-fluorophenyl isocyanate (25.6 μl, 0.225 mmol) wassuccessively added thereto while being cooled with ice. The mixture wasstirred at the same temperature for 30 minutes, to which methanol (30μl) and triethylamine (30 μl) were added, and was further stirred for 30minutes. The reaction solution was concentrated under reduced pressure,and the resultant residue was washed with toluene to give the titlecompound (73 mg, yield 86%) as colorless crystals (Table 31).

EXAMPLE 8-2

[0314]N-](8-Butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-yl)-methyl]-(4-hydroxyphenyl)acetamide

[0315] 8-Butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (77.7mg, 0.281 mmol) obtained in Example 7-2, 4-hydroxyphenylacetic acid(47.0 mg, 0.309 mmol) and N-hydroxybenzotriazole (41.8 mg, 0.309 mmol)were dissolved in DMF (3 ml), and EDC (59.2 mg, 0.309 mmol) andtriethylamine (30 μl) were successively added thereto. The mixture wasstirred at 50° C. for 3 hours, and then a saturated aqueous solution ofsodium bicarbonate (3 ml) and toluene (5 ml) were added thereto. Theprecipitated crystals were collected through filtration, and washedsuccessively with water, 1 N hydrochloric acid, water, and ethyl acetateto give the title compound (88 mg, yield 76%) as colorless crystals(Table 32). TABLE 1 Ref. Ex. No./structure/character/mp (° C.) 1H NMR(δ) ppm IR cm⁻¹ MS

CDCl3, 300MHz 9.80(1H, s) 7.64(1H, d, J=8.6Hz) 7.09(1H, d, J=8.6Hz)4.11(2H, t, J=6.6Hz) 3.99(3H, s) 1.60-1.80(2H, m) 1.28-1.47(4H, m)0.92(3H, t, J=7.1Hz) FAB+268[M + H +](80) 198 (100)

CDCl3, 300MHz 9.52(1H, s) 7.22(1H, d, J=9.0Hz) 6.90(1H, d, J=9.0Hz)4.41(2H, t, J=6.9Hz) 3.97(3H, s) 2.0-2.3(2H, bs) 1.7-1.9(2H, m)1.3-1.5(4H, m) 0.92(3H, t, J=7.2Hz) FAB+238[M + H +](100)

CDCl3, 300MHz 9.84(s, 1H) 7.45(s, 1H) 7.43(d, 1H, J=8.7Hz) 6.98(d, 1H,J=8.7Hz) 6.40(bs, 1H) 4.00(s, 3H) FAB+153[M + H +](100)

[0316] TABLE 2 Ref. Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppmIR cm⁻¹ MS

DMSO-d6, 300MHz 10.91(bs, 1H) 9.57(s, 1H) 7.59(d, 1H, J=8.4Hz) 7.35(d,1H, J=8.4Hz) 3.99(3H, s) FAB−232[M + H +](20) 185(100)

DMSO-d6, 300MHz 10.91(bs, 1H) 10.18(s, 1H) 7.83(s, 1H) 7.22(s, 1H)3.96(3H, s) FAB−232[M + H +](20) 185(100)

CDCl3, 300MHz 9.79(s, 1H) 7.64(d, 1H, J=8.6Hz) 7.06(d, 1H, J=8.6Hz)4.09(t, 2H, J=6.7Hz) 4.00(s, 3H) 1.7-1.8(m, 2H) 1.3-1.5(m, 4H) 0.92(t,3H, J=7.1Hz)

[0317] TABLE 3 Ref. Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppmIR cm⁻¹ MS

CDCl3, 300MHz 10.43(s, 1H) 7.61(s, 1H), 7.39(s, 1H) 4.16(t, 2H, J=6.7Hz)4.16(s, 3H) 1.8-2.0(m, 2H) 1.3-1.5(m, 4H) 0.94(t, 3H, J=6.9Hz)

CDCl3, 300MHz 9.50(bs, 2H) 7.81(s, 1H) 7.38(d, 1H, J=8.4Hz) 7.00(d, 1H,J=8.4Hz) 4.05(t, 2H, J=6.9Hz) 3.93(s, 3H) 1.6-1.9(m, 2H) 1.3-1.5(m, 4H)0.91(t, 3H, J=6.9Hz) FAB+354[M + H +](100)

CDCl3, 300MHz 9.50(bs, 2H) 8.67(s, 1H) 7.76(s, 1H) 6.82(s, 1H) 4.10(t,2H, J=6.9Hz) 3.97(s, 3H) 1.8-2.0(m, 2H) 1.3-1.5(m, 4H) 0.91(t, 3H,J=6.9Hz) FAB+354[M + H +](100)

[0318] TABLE 4 Ref. Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppmIR cm⁻¹ MS

CDCl3, 300MHz 7.53(s, 1H) 7.19(d, 1H, J=8.8Hz) 6.97(d, 1H, J=8.8Hz)4.04(t, 2H, J=6.8Hz) 3.93(s, 3H) 3.83(s, 3H) 3.79(s, 3H) 1.7-1.8(m, 2H)1.3-1.5(m, 4H) 0.92(t, 3H, J=7.0Hz) FAB+382[M − H +](100)

CDCl3, 300MHz 8.22(s, 1H) 7.76(s, 1H) 6.85(s, 1H) 4.11(t, 2H, J=6.7Hz)3.97(s, 3H) 3.88(s, 3H) 3.66(s, 3H) 1.8-2.0(m, 2H) 1.3-1.5(m, 4H)0.94(t, 3H, J=6.8Hz) FAB+382[M − H +](100)

[0319] TABLE 5 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3, 300MHz 9.04(1H, bs) 8.50(1H, s) 7.36(1H, d, J=9.0Hz) 6.88(1H, d,J=9.0Hz) 4.13(2H, t, J=6.9Hz) 3.96(3H, s) 3.74(3H, s) 1.7-1.9(2H, m)1.3-1.5(4H, m) 0.94(3H, t, J=7.2Hz) KBr 3423 2952 1742 1642 1505 1269FAB+320(M + H +) (100) 288(70)

CDCl3, 300MHz 12.6(s, 1H) 8.54(s, 1H) 6.98(s, 1H) 6.95(s, 1H) 4.04(t,2H, J=6.9Hz) 4.04(s, 3H) 3.70(s, 3H) 1.8-2.0(m, 2H) 1.3-1.6(m, 4H)0.95(t, 3H, J=6.9Hz) KBr 3444 2953 1730 1645 1571 1511 1484 1421 12691228 1900 FAB+320(M + H +) (100) 288(100)

CDCl3, 300MHz 8.33(s, 1H) 7.36(d, 1H, J=8.7Hz) 6.92(d, 1H, J=8.7Hz)3.98(s, 3H) 3.97(s, 3H) 3.94(s, 3H) 3.85(t, 2H, 6.8Hz) 1.7-1.9(m, 2H)1.3-1.5(m, 4H) 0.93(t, 3H, J=6.9Hz) KBr 2938 1703 1659 1613 1590 15001453 1274 1059  800 FAB+334[M − H +](100)

[0320] TABLE 6 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

DMSO-d6, 300MHz 8.42(s, 1H) 7.44(s, 1H) 6.97(s, 1H) 3.98(t, 2H, J=6.6Hz)3.97(s, 3H) 3.78(s, 3H) 3.65(s, 3H) 1.7-1.9(m, 2H) 1.3-1.5(m, 4H)0.90(t, 3H, J=6.8Hz) KBr 2948 1736 1260 1080  795 FAB+334(M + H +) (100)302(100)

CDCl3, 300MHz 14.00(1H, s) 9.42(1H, bs) 8.87(1H, s) 7.51(1H, d, J=9.0Hz)7.03(1H, d, J=9.0Hz) 4.18(2H, t, J=6.9Hz) 4.01(3H, s) 1.7-1.8(2H, m)1.3-1.5(4H, m) 0.95(3H, t, J=6.9Hz) KBr 3423 2952 1742 1642 1505 1269FAB+306[M + H +](100)

CDCl3, 300MHz 14.98(br s, 1H) 9.51(br s, 1H) 8.87(s, 1H) 7.51(d,J=9.0Hz, 1H) 7.04(d, J=9.0Hz, 1H) 4.20(t, J=6.9Hz, 2H) 4.02(s, 3H)1.81(m, 2H) 1.51(m, 2H) 1.00(t, J=6.9Hz, 3H) KBr 1723 1630 1506 12831258 1099

[0321] TABLE 7 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3, 300MHz 14.00(br s, 1H) 9.71(br s, 1H) 8.88(s, 1H) 7.52(d,J=9.0Hz, 1H) 7.04(d, J=9.0Hz, 1H) 4.29(q, J=6.9Hz, 2H) 4.02(s, 3H)1.44(t, J=6.9Hz, 3H) KBr 1736 1634 1504 1474 1282 1259 1095

DMSO-d6, 300MHz 12.37(brs, 1H) 8.90(s, 1H) 7.81(d, 1H, J=9.2Hz) 7.27(d,1H, J=9.2Hz) 3.97(m, 5H) 1.80(q, 2H, J=7.3Hz) 0.95(t, 3H, J=7.6Hz) KBr3188 1735 1630 1507 1286

DMSO-d6, 300MHz 14.96(s, 1H) 13.05(s, 1H) 8.81(s, 1H) 7.55(s, 1H)7.01(s, 1H) 4.01(t, 2H, J=6.6Hz) 3.90(s, 3H) 1.7-1.9(m, 2H) 1.3-1.5(m,4H) 0.91(t, 3H, J=6.8Hz) KBr 3422 1685 1211 FAB+305(M +H +)(100)

[0322] TABLE 8 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

DMSO-d6, 300MHz 14.58(s, 1H) 8.76(s, 1H) 7.52(d, 1H, J=8.8Hz) 7.07(d,1H, J=8.8Hz) 4.02(s, 3H) 3.93(s, 3H) 3.91(r, 2H, J=6.9Hz) 1.7-1.9(m, 2H)1.3-1.5(m, 4H) 0.95(t, 3H, J=7.1Hz) KBr 2956 1735 1622 1560 1509 14581379 1280 1067 FAB+320(M + H +) (100) 302(100)

CDCl3, 300MHz 14.70(s, 1H) 8.78(s, 1H) 7.11(s, 1H) 6.83(s, 1H) 4.08(t,2H, J=6.8Hz) 4.06(s, 3H) 3.86(s, 3H) 1.8-2.0(m, 2H) 1.3-1.5(m, 4H)0.95(t, 3H, J=7.1Hz) KBr 3448 1718 1654 1560 1508 1271 FAB+320(M + H +)(50) 302(100)

CDCl3, 300MHz 9.74(1H, bt) 9.13(1H, bs) 8.49(1H, s) 8.53(2H, d, J=6.0Hz)7.46(1H, d, J=8.9Hz) 7.22(2H, d, J=6.0Hz) 6.94(1H, d, J=8.9Hz) 4.14(2H,t, J=6.9Hz) 3.98(3H, s) 3.76(2H, q, J=6.7Hz) 2.97(2H, t, J=7.2Hz)1.74-1.88(2H, m) 1.35-1.53(4H, m) 0.95(3H, t, J=7.1Hz) KBr 3257 29381672 1622 1530 1261 1112  805 FAB+410[M + H +](60) 288(60)

[0323] TABLE 9 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3, 300MHz 9.87(1H, br) 9.10(1H, bs) 8.89(1H, s) 7.45(1H, d, J=8.8Hz)7.18(2H, d, J=8.3Hz) 6.93(1H, d, J=8.8Hz) 6.66(2H, d, J=8.3Hz) 4.56(2H,d, J=6.0Hz) 4.13(2H, t, J=6.9Hz) 3.97(3H, s) 1.71-1.87(2H, m)1.30-1.50(4H, m) 0.94(3H, t, J=7.1Hz) KBr 3232 2954 1668 1622 1520 12601109  801 FAB+410[M + H +](40) 288 (20)

CDCl3, 300MHz 9.63(1H, br) 9.10(1H, bs) 8.85(1H, s) 7.44(1H, d, J=8.7Hz)7.07(2H, d, J=8.4Hz) 6.93(1H, d, J=8.7Hz) 6.66(1H, d, J=8.4Hz) 4.13(2H,r, J=6.8Hz) 3.97(3H, s) 3.67(2H, q, J=6.8Hz) 2.83(2H, t, J=7.2Hz)1.75-1.88(2H, m) 1.30-1.50(4H, m) 0.95(3H, t, J=7.2Hz) KBr 3248 29281672 1625 1539 1260 1112  802 FAB+424[M + H +](40)

DMSO-d6, 300MHz 12.1(1H, s) 11.7(1H, s) 8.88(1H, s) 7.77(2H, d, J=9.0Hz)7.75(1H, d, J=9.0Hz) 7.26(2H, d, J=9.0Hz) 7.18(1H, d, J=9.0Hz) 4.00(2H,t, J=6.9Hz) 1.70-1.83(2H, m) 1.30-1.50(4H, m) 0.89(3H, t, J=7.2Hz) KBr2954 1672 1622 1552 1498 1284 1263 FAB+296(30) 288(100) 218(70)

[0324] TABLE 10 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3, 300MHz 13.99 9.18(br, 1H) 9.18(s, 1H) 8.90(s, 1H) 7.47(d, 1H,J=8.8Hz) 6.95(d, 1H, J=8.8Hz) 6.8-6.9(m, 2H) 6.77(d, 1H, J=7.9Hz)5.95(s, 2H) 4.59(d, 2H, J=5.8Hz) 4.14(t, 2H, J=8.7Hz) 3.99(s, 3H)1.7-1.9(m, 2H) 1.3-1.5(m, 4H) 0.95(t, 3H, J=7.1Hz) KBr 2956 1684 16191535 1263 FAB+439[M + H +](100)

CDCl3, 300MHz 9.80(br t, J=5.9Hz, 1H) 9.21(br s, 1H) 8.81(s, 1H) 8.58(d,J=5.9Hz, 2H) 7.53(d, J=6.2Hz, 2H) 7.47(d, J=8.8Hz, 1H) 6.96(d, J=8.8Hz,1H) 4.25(q, J=7.1Hz, 2H) 3.99(s, 3H) 3.83(q, J=6.6Hz, 2H) 3.12(t,J=7.0Hz, 2H) 1.43(t, J=7.1Hz, 3H) KBr 1672 1626 1538 1500 1375 1286 12601223 1115 (ESI+) 368 264 246 (ESI−) 366 323

9.71(br, 1H) 9.18(s, 1H) 8.86(s, 1H) 7.44(d, 1H, J=8.7Hz) 7.12(d, 2H,J=8.4Hz) 6.93(d, 1H, J=8.4Hz) 6.80(d, 2H, J=8.4Hz) 6.23(s, 1H) 4.12(t,2H, J=6.6Hz) 3.97(s, 3H) 3.70(q, 2H, J=7.2Hz) 2.87(t, 2H, J=7.2Hz)1.7-1.9(m, 2H) 1.3-1.5(m, 4H) 0.94(t, 3H, J=7.2Hz) KBr 3246 2932 16731625 1537 1515 1500 1262 1110 FAB+425(M + H +) (100) 288(75)

[0325] TABLE 11 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

9.67(bt, 1H) 9.11(s, 1H) 8.85(s, 1H) 7.45(d, 1H, J=8.7Hz) 7.2-7.3(m, 2H)7.00(t, 2H, J=8.7Hz) 6.93(d, 1H, J=8.7Hz) 4.13(t, 2H, J=6.9Hz) 3.97(s,3H) 3.97(q, 2H, J=7.2Hz) 2.92(t, 2H, J=7.2Hz) 1.7-1.9(m, 2H) 1.3-1.6(m,4H) 0.95(t, 3H, J=6.9Hz) KBr 3286 # 2962 1661 1614 1533 1497 1262FAB+427(M + H+) (100) 288(40)

CDCl3,300MHz 10.16(br, 1H) 9.26(s, 1H) 8.90(s, 1H) 8.55(d, 2H, J=6.8Hz)7.47(d, 1H, J=8.8) 7.28(d, 2H, J=6.8) 6.87(d, 1H, J=8.8Hz) 4.70(t, 2H,J=6.0Hz) 4.15(t, 2H, J=6.9Hz) 3.99(s, 3H) 1.7-1.9(m, 2H) 1.3-1.5(m, 4H)0.95(t, 3H, J=6.9Hz) KBr 2956 # 1684 1619 1535 1263 FAB+396(M + H+)(100) 288(40)

CDCl3,300MHz 9.76(bt, 1H) 9.12(s, 1H) 8.85(s, 1H) 7.44(d, 1H, J=9.0Hz)6.93(d, 1H, J=9.0Hz) 4.13(t, 2H, J=6.9Hz) 3.97(s, 3H) 3.60(q, 2H,J=6.6Hz) 2.59(t, 2H, J=6.6Hz) 2.4-2.5(m, 4H) 1.7-1.9(m, 2H) 1.5-1.7(m,4H) 1.3-1.5(m, 6H) 0.95(t, 3H, J=6.9 #Hz) Neat 2932 1667 1537 1504FAB+416(M + H+) (100) 331(50) 288(40)

[0326] TABLE 12 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3,300MHz 9.81(bt, 1H) 9.13(s, 1H) 8.86(s, 1H) 7.45(d, 1H, J=8.9Hz)6.94(d, 1H, J=8.9Hz) 4.13(t, 2H, J=6.9Hz) 3.98(s, 3H) 3.7-3.8(m, 4H)3.61(q, 2H, J=6.4Hz) 2.62(t, 2H, J=6.4Hz) 2.5-2.6(m, 4H) 1.7-1.9(m, 2H)1.4-1.5(m, 4H) 0.95(t, 3H, #J=71 Hz) KBr 3438 2953 1718 1639 1507 14861287 FAB+418(M + H+) (100)

CDCl3,300MHz 10.07(bt, 1H) 9.16(s, 1H) 8.89(s, 1H) 8.64(s, 1H) 8.52(d,1H, J=1.7Hz) 7.7(d, 1H, J=7.9Hz) 7.47(t, 1H, J=8.8Hz) 7.26(dd, 1H,J=7.9, 1.7Hz) 6.95(d, 1H, J=8.8Hz) 4.70(d, 2H, J=6.0Hz) 4.14(t, 2H,J=6.9Hz) 3.98(s, 3H) 1.7-1.9 #(m, 2H) 1.3-1.5(m, 4H) 0.94(t, 3H,J=7.1Hz) KBr 2956 1684 1618 1537 1264 FAB+396(M + H+) (100) 288(40)

CDCl3,300MHz 10.35(bt, 1H) 9.17(s, 1H) 8.90(s, 1H) 8.60(d, 1H, J=4.7Hz)7.65(dt, 1H, J=7.7, 1.7Hz) 7.46(d, 1H, J=8.9Hz) 7.61(t, 1H, J=7.7Hz)7.16(dt, 1H, J=4.7, 1.7Hz) 6.94(d, 1H, J=8.9Hz) 4.84(t, 2H, J=5.6Hz)4.14(t, 2H, J=6.9Hz) 3.98(s, 3H) 1.7-1.9 #(m, 2H) 1.3-1.5(m, 4H) 0.94(t,3H, J=6.9Hz) KBr 2931 1668 1622 1526 1262 FAB+396(M + H+) (100) 288(40)

[0327] TABLE 13 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3,300MHz 9.97(9.97(br t, J=5.9Hz, 1H) 9.12(br s, 1H) 8.86(s, 1H)7.45(d, J=8.8Hz, 1H) 7.35-7.23(m, 5H) 6.93(d, J=8.8Hz, 1H) 4.14(t, J=70Hz, 2H) 3.97(s, 3H) 3.74(q, J=6.8Hz, 2H) 2.95(t, J=7.1Hz, 2H)1.81(quintet, J=7.1Hz, 2H) 1.51(m, 2H) 1.00 #(t, J=7.3Hz, 3H)br t,J=5.9Hz, 1H) KBr 1660 1613 1535 1375 1260 1133 (fab+, NBA) 395 274 218(fab−, NBA) 393 305 153

CDCl3,300MHz 9.67(br t, J=5.9Hz, 1H) 9.12(br s, 1H) 8.85(s, 1H) 7.45(d,J=8.8Hz, 1H) 7.24(m, 2H) 7.00(m, 2H) 6.93(d, J=8.8Hz, 1H) 4.14(t,J=7.0Hz, 2H) 3.97(s, 3H) 3.71(q, J=6.8Hz, 2H) 2.92(t, J=7.1Hz, 2H)1.80(quintet, J=7.1Hz, 2H) 1.51 #(m, 2H) 1.00(t, J=7.3Hz, 3H) 2964 16611613 1532 1376 1259 1111 (fab+, (NBA) 413 274 218 (fab−, NBA) 411 305153

CDCl3,300MHz 9.73(br t, J=5.9Hz, 1H) 9.14(br s, 1H) 8.85(s, 1H) 8.53(d,J=6.2Hz, 2H) 7.45(d, J=8.8Hz, 1H) 7.21(d, J=5.9Hz, 2H) 6.94(d, J=8.8Hz,1H) 4.15(t, J=69 Hz, 2H) 3.98(s, 3H) 3.76(q, J=6.7Hz, 2H) 2.96(t,J=7.3Hz, 2H) 1.80(quintet, #J=7.5Hz, 2H) 1.51(m, 2H) 1.00(t, J=7.3Hz,3H) KBr 1676 1626 1537 1499 1370 1284 1260 1113 (fab+, NBA) 396 274 218(fab−, NBA) 394 305 153

[0328] TABLE 14 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

DMSO-d6,300MHz (br s, 1H) 9.79(t, J=5.9Hz, 1H) 8.84(d, J=6.6Hz, 2H,J=6.6Hz) 8.72(s, 1H) 8.00(d, J=6.6Hz, 2H) 7.68(d, J=8.8Hz, 1H) 7.13(d,J=8.8Hz, 1H) 3.99(t, J=6.9Hz, 2H) 3.93(s, 3H) 3.75(q, J=6.5Hz, 2H)3.19(t, J=6.6Hz, 2H) 1.76 #(quintet, J=7.3Hz, 2H) 1.41(m, 2H) 0.93(t,J=7.3Hz, 3H) KBr 1676 1626 1537 1499 1370 1284 1260 1113 (ESI+) 396 292274 (ESI−) 394 338 322

CDCl3,300MHz 9.67(br t, J=5.9Hz, 1H) 9.17(br s, 1H) 8.86(s, 1H) 7.46(d,J=8.8Hz, 1H) 7.24(m, 2H) 7.00(m, 2H) 6.94(d, J=8.8Hz, 1H) 4.23(q,J=7.1H, 2Hz) 3.98(s, 3H) 3.70(q, J=7.1Hz, 2H) 2.9(t, J=7.1Hz, 2H)1.42(t, J=7.0Hz, 3H) KBr 1666 # 1626 1509 1262 1218 1114 (ESI+) 385 264246 (ESI−) 383 355 341

CDCl3,300MHz 9.65(br, 1H) 9.12(s, 1H) 8.82(s, 1H) 7.40(d, 1H, J=8.8Hz)6.9-7.3(m, 4H) 6.90(d, 1H, J=8.8Hz) 4.09(t, 2H, J=6.6Hz) 3.93(s, 3H)3.67(q, 2H, J=7.0Hz) 2.96(t, 2H, J=7.0Hz) 1.7-1.9(m, 2H) 1.3-1.5(m, 4H)0.91(t, #3H, J=7.0Hz) KBr 3235 2951 1663 1611 1530 1483 1286 FAB+427(M +H+) (100)

[0329] TABLE 15 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

9.69(bt, 1H) 9.16(s, 1H) 8.86(s, 1H) 7.45(d, 1H, J=9.0Hz) 7.2-7.4(m, 1H)6.93(d, 1H, J=9.0Hz) 6.8-7.1(m, 3H) 4.13(t, 2H, J=6.9Hz) 3.97(s, 3H)3.72(q, 2H, J=7.2Hz) 2.95(t, 2H, J=7.2Hz) 1.7-1.9(m, 2H) 1.3-1.5(m, #4H)0.94(t, 3H, J=6.9Hz) KBr 3134 2958 1670 1626 1535 1482 1286 FAB+427(M +H+) (100)

CDCl3,300MHz 9.71(bt, 1H) 9.16(s, 1H) 8.67(s, 1H) 7.47(d, 1H, J=8.8Hz)6.89(d, 1H, J=7.9Hz) 6.7-6.9(m, 3H) 5.61(s, 1H) 4.15(t, 2H, J=6.9Hz)3.99(s, 3H) 3.90(s, 3H) 3.70(q, 2H, J=7.4Hz) 2.89(t, 2H, #J=7.4Hz)1.7-1.9(m, 2H) 1.3-1.5(m, 4H) 0.96(t, 3H, J=7.1Hz) 3310 2952 1672 16251598 1529 1516 1260 FAB+455(M + H+) (100)

CDCl3,300MHz 9.70(br, 1H) 9.16(s, 1H) 8.85(s, 1H) 7.45(d, 1H, J=8.9Hz)7.27(d, 2H, J=8.4Hz) 7.20(d, 2H, J=8.4Hz) 6.93(d, 1H, J=8.9Hz) 4.13(t,2H, J=6.9Hz) 3.87(s, 3H) 3.70(q, 2H, J=7.0Hz) 2.92(t, 2H, #J=7.0Hz)1.7-1.9(m, 2H) 1.3-1.5(m, 4H) 0.95(t, 3H, J=7.0Hz) KBr 3286 2960 16611613 1530 1496 1261 FAB+443(M + H+) (100)

[0330] TABLE 16 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3,300MHz 9.67(bt, 1H) 9.12(s, 1H) 8.86(s, 1H) 7.45(d, 1H, J=8.7Hz)7.2-7.4(m, 5H) 6.93(d, 1H, J=8.7Hz) 4.13(t, 2H, J=6.9Hz) 3.97(s, 3H)3.74(q, 2H, J=7.2Hz) 2.95(t, 2H, J=7.2Hz) 1.7-1.9(m, #2H) 1.3-1.5(m, 4H)0.95(t, 3H, J=7.2Hz) KBr 3249 3139 2951 1661 1610 1284 1261 1116FAB+409(M + H+) (100)

CDCl3,300MHz 9.99(bt, 1H) 9.21(s, 1H) 8.91(s, 1H) 7.46(d, 1H, J=8.9Hz)7.28(d, 2H, J=7.9Hz) 7.15(d, 2H, J=7.9Hz) 6.94(d, 1H, J=8.9Hz) 4.66(d,2H, J=5.7Hz) 4.14(t, 2H, J=6.9Hz) 3.98(s, 3H) 2.34 #(s, 3H) 1.7-1.9(m,2H) 1.3-1.5(m, 4H) 0.95(t, 3H, J=7.1Hz) KBr 3263 3417 1663 1618 15961587 1265 1262 1110 FAB+408(M + H+) (100)

CDCl3,300MHz 10.01(bt, 1H) 9.13(s, 1H) 8.99(s, 1H) 7.47(d, 1H, J=8.9Hz)7.3-7.4(m, 2H) 7.01(t, 2H, J=8.7Hz) 6.94(d, 1H, J=8.9Hz) 4.64(d, 2H,J=5.8Hz) 4.14(t, 2H, J=6.9Hz) 3.98(s, 3H) 1.7-1.9 #(m, 2H) 1.3-1.5(m,4H) 0.94(t, 3H, J=7.1Hz) KBr 3242 1664 1619 1537 1510 1263 FAB+413(M +H+) (100)

[0331] TABLE 17 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

DMSO-d6,300MHz 11.42(brs, 1H) 9.76(t, 1H, J=5.4Hz) 8.75(s, 1H) 8.47(d,2H, J=6.0Hz) 7.68(d, 1H, 9.3Hz) 7.30(d, 2H, J=5.7Hz) 7.13(d, 1H,J=9.0Hz) 3.95(m, 5) 3.64(q, 2H, J=6.3Hz) 2.88(t, #2H, 6.9Hz) 1.78(m, 2H)0.94(t, 3H, J=7.2Hz) KBr 1671 1627 1537 1374 1265 (FAB+) 382(M + H+)(80)

DMSO-d6.300MHz 11.42(brs, 1H) 9.75(t, 1H, J=6.0Hz) 8.75(s, 1H) 7.68(d,1H, J=8.7Hz) 7.31(m, 2H) 7.12(m, 3H) 3.95(m, 5H) 3.58(q, 2H, J=6.3Hz)2.84(t, 2H, J=6.9Hz) 1.78(m, 2H) 0.94(t, 3H, J= #7.2Hz) KBr 2961 16661624 1536 1219 (FAB+) 399(M + H+) (90)

DMSO-d6,300MHz 11.40(brs, 1H) 9.73(t, 1H, 5.4Hz) 9.16(s, 1H) 8.74(s, 1H)7.68(d, 1H, J=9.3Hz) 7.12(d, 1H, J=9.3Hz) 7.06(d, 2H, J=8.4Hz) 6.68(d,2H, J=8.4Hz) 3.95(m, 5H) 3.52(q, 2H, J=6.0Hz) 2.72 #(t, 2H, J=6.9Hz)1.78(m, 2H) 0.94(t, 3H, J=7.2Hz) KBr 3236 1668 1611 1538 1261 (FAB+)397(M + H+) (70)

[0332] TABLE 18 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

DMSO-d6,300MHz 11.41(brs, 1H) 10.04(t, 1H, J=5.7Hz) 8.79(s, 1H) 7.70(d,1H, J=8.7Hz) 7.14(d, 1H, J=8.7Hz) 6.86(m, 3H) 5.99(s, 2H) 4.47(d, 2H,J=5.7Hz) 3.96(m, 5H) 1.79(m, 2H) 0.94(t, 3H, #J=7.5Hz) KBr 2967 16641618 1535 1259 (FAB+) 411(M + H+) (80)

DMSO-d6,300MHz 11.41(brs, 1H) 9.77(t, 1H, J=6.0Hz) 8.75(s, 1H) 7.68(d,1H, J=8.7Hz) 7.26(m, 5H) 7.13(d, 1H, J=8.7Hz) 3.95(m, 5H) 3.59(q, 2H,J=5.7Hz) 2.85(t, 2H, J=7.2Hz) 1.78(m, 1H) 0.94(t, #3H, J=7.5Hz) KBr 16661625 1537 1261 1113 (FAB+) 381(M + H+) (100)

CDCl3,300MHz 9.65(bt, 1H) 9.26(s, 1H) 8.86(s, 1H) 7.47(d, 1H, J=8.7Hz)7.2-7.3(m, 2H) 7.00(t, 2H, J=8.4Hz) 6.94(d, 1H, J=8.7Hz) 4.00(S, 3H)3.98(s, 3H) 3.70(q, 2H, J=7.2Hz) 2.92(t, 2H, #J=7.2Hz) KBr 3650 32501664 1509 1221 FAB+371(M + H+) (100) 232(90)

[0333] TABLE 19 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

DMSO-d6,300MHz 12.24(s, 1H) 9.89(bt, 1H) 7.45(s, 1H) 7.2-7.4(m, 2H)7.11(t, 2H, J=8.9Hz) 6.90(s, 1H) 3.99(t, 2H, J=6.6Hz) 3.86(s, 3H)3.55(q, 2H, J=7.3Hz) 2.83(t, 2H, J=7.3Hz) 1.7-1.9 #(m, 2H) 1.3-1.5(m,4H) 0.90(t, 3H, J=7.0Hz) KBr 3448 1670 1560 1508 1266 FAB+427(M + H+)(100)

CDCl3,300MHz 10.75(s, 1H) 10.00(bt, 1H) 8.88(s, 1H) 7.08(s, 1H)6.7-6.9(m, 3H) 6.64(s, 1H) 5.93(s, 2H) 4.61(d, 2H, J=5.8Hz) 4.05(t, 2H,J=6.8Hz) 3.98(s, 3H) 1.8-2.0(m, 2H) 1.3-1.5 #(m, 4H) 0.95(t, 3H,J=7.1Hz) 3448 1671 1509 1266 FAB+439(M + H+) (100)

DMSO-d6,300MHz 12.21(s, 1H) 9.98(br, 1H) 8.71(s, 1H) 7.45(s, 1H) 6.90(s,1H) 3.98(t, 2H, J=6.9Hz) 3.86(s, 3H) 3.5-3.7(m, 4H) 3.4-3.5(m, 2H)2.6-2.7(m, 2H) 2.5-2.6(m, 4H) 1.6-1.9 #(m, 2H) 1.2-1.5(m, 4H) 0.93(t,3H, J=7.0Hz) KBr 3448 1676 1244 FAB+418(M + H+) (100)

[0334] TABLE 20 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

DMSO-d6,300MHz 11.54(brs, 1H) 10.05(t, 1H, J=5.9Hz) 8.79(s, 1H) 7.70(d,1H, J=8.8Hz) 7.14(d, 1H, J=8.8Hz) 6.87(m, 3H) 5.99(s, 2H) 4.47(d, 2H,J=5.9Hz) 4.07(q, 2H, J=7.0Hz) 3.93(s, 3H) 1.32(t, #3H, J=7.0Hz) KBr 31681673 1619 1536 1257 1106 (FAB+) 397(M + H+) (80)

CDCl3,300MHz 9.90(bt, 1H) 8.74(s, 1H) 7.46(d, 1H, J=8.7Hz) 7.2-7.3(m,2H) 6.9-7.1(m, 2H) 6.97(d, 1H, J=8.7Hz) 4.11(s, 3H) 4.09(s, 3H) 3.86(t,2H, J=6.8Hz) 3.69(q, 2H, J=7.3Hz) 2.92(t, 2H, #J=7.3Hz) 1.7-1.9(m, 2H)1.3-1.6(m, 4H) 0.94(t, 3H, J=7.1Hz) 3231 2953 1673 1612 1535 1530 12701219 FAB+441(M + H+) (100) 302(90)

CDCl3,300MHz 9.97(br, 1H) 8.74(s, 1H) 8.52(d, 2H, J=5.9Hz) 7.48(d, 1H,J=8.8Hz) 7.21(,d 2H, J=5.9Hz) 6.99(d, 1H, J=8.8Hz) 4.00(s, 3H) 3.98(s,3H) 3.87(t, 2H, J=6.8Hz) 3.75(q, 2H, J=7.2Hz) 2.96 #(t, 2H, J=7.2Hz)1.7-1.9(m, 2H) 1.3-1.5(m, 4H) 0.94(t, 3H, J=7.1Hz) KBr 3448 2955 16721611 1579 1334 1452 1270 FAB+424(M + H+) (100)

[0335] TABLE 21 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3,300MHz 9.96(bt, 1H) 8.74(s, 1H) 7.46(d, 1H, J=8.7Hz) 6.97(d, 1H,J=8.7Hz) 4.02(s, 3H) 3.98(s, 3H) 3.85(t, 2H, J=6.6Hz) 3.7-3.8(m, 4H)3.61(q, 2H, J=6.6Hz) 2.62(t, 2H, J=6.6Hz) 2.5-2.6(m, 4H) 1.8-1.9(m, 2H)1.3-1.5(m, 4H) 0.94(t, 3H, J= #7.2Hz) KBr 3448 2948 1672 1612 1581 15601535 1452 1269 FAB+432(M + H+) (100)

CDCl3,300MHz 10.38(br 1H) 8.78(s, 1H) 8.55(d, 2H, J=6.8Hz) 7.49(d, 1H,J=8.7Hz) 7.28(d, 2H, J=6.8) 7.00(d, 1H, J=8.7Hz) 4.69(t, 2H, J=6.0Hz)4.08(s, 3H) 3.99(s, 3H) 3.89(t, 2H, J=6.8Hz) 1.7-1.9(m, 2H) 1.3-1.5(m,4H) 0.95(t, 3H, J= #7.1Hz) KBr 3264 2957 1668 1609 1579 1526 1286FAB+410(M + H+) (100)

CDCl3,300MHz 10.22(bt, 1H) 8.78(s, 1H) 7.48(d, 1H, J=8.7Hz) 7.3-7.4(m,2H) 7.02(d, 1H, J=8.7Hz) 6.9-7.0(m, 3H) 4.64(d, 2H, J=5.8Hz) 4.00(s, 3H)3.98(s, 3H) 3.87(t, 2H, J=6.9Hz) 1.7-1.9(m, 2H) 1.3-1.5(m, 4H) 0.94(t,3H, J= #6.9Hz) KBr 3448 1688 1610 1579 1560 1528 1288 FAB+427(M + H+)(100)

[0336] TABLE 22 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3,300MHz 10.01(bt, 1H) 8.75(s, 1H) 7.46(d, 1H, J=8.8Hz) 7.08(d, 2H,J=8.4Hz) 6.73(d, 1H, J=8.8Hz) 6.79(d, 2H, J=8.4Hz) 6.90(bs, 1H) 4.00(s,3H) 3.98(s, 3H) 3.86(t, 2H, J=6.8Hz) 3.68(q, 2H, J=7.2Hz) 2.86(t, 2H,J=7.2Hz) 1.7-1.9(m, #2H) 1.3-1.5(m, 4H) 0.94(t, 3H, J=7.1Hz) KBr 32462939 1672 1606 1536 1514 1500 1270 FAB+439(M + H+) (100)

CDCl3,300MHz 10.15(bt, 1H) 8.77(s, 1H) 7.47(d, 1H, J=8.8Hz) 6.98(d, 1H,J=8.8Hz) 6.87(d, 1H, J=1.5Hz) 6.84(dd, 1H, J=7.7, 1.5Hz) 6.75(d, 1H,J=7.7Hz) 5.92(s, 2H) 4.57(d, 2H, J=5.5Hz) 4.00(s, 3H) 3.98(s, 3H)3.87(t, 2H, J=7.0Hz) 1.7- #1.9(m, 2H) 1.3-1.5(m, 4H) 0.94(t, 3H,J=7.0Hz) KBr 2930 1268 800 FAB+453(M + H+) (100) 302(100)

CDCl3,300MHz 10.00(bt, 1H) 8.77(s, 1H) 7.2-7.3(m, 2H) 7.10(s, 1H)6.99(t, 2H, J=8.6Hz) 6.77(s, 1H) 4.07(t, 2H, J=7.0Hz) 4.02(s, 3H)3.77(s, 3H) 3.70(q, 2H, J=7.7Hz) 2.92(t, 2H, J=7.7Hz) 1.7-2.0(m, 2H)1.3-1.6(m, 4H) 0.95(t, #3H, J=6.9Hz) KBr 2935 1672 1510 1426 1260FAB+442(M + H+) (100) 302(100)

[0337] TABLE 23 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3.300MHz 10.06(bt, 1H) 8.77(s, 1H) 7.10(s, 1H) 6.77(s, 1H) 4.07(t,2H, J=7.0Hz) 4.03(s, 3H) 3.78(s, 3H) 3.6-3.7(m, 4H) 3.62(q, 2H, J=6.6Hz)2.63(t, 2H, J=6.6Hz) 2.5-2.6(m, 4H) 1.8-2.0(m, 2H) 1.3-1.6(m, 4H)0.95(t, 3H, #J=7.0Hz) KBr 2934 1672 1609 1543 1430 1397 1260 1171 1120FAB+432(M + H+) (100) 302(100)

CDCl3,300MHz 10.24(t, 1H, J=5.9Hz) 8.81(s, 1H) 7.11(s, 1H) 6.88(s, 1H)6.84(d, 1H, J=8.1Hz) 6.78(s, 1H) 6.75(d, 1H, J=8.1Hz) 5.92(s, 1H)4.58(d, 2H, J=5.9Hz) 4.07(t, 2H, J=7.0Hz) 4.02(s, 3H) 3.76(s, 3H)1.8-2.0(m, 2H) 1.3- #1.6(m, 4H) 0.95(t, 3H, J=7.0Hz) KBr 3448 1671 15421251 FAB+453(M + H+) (100) 302(100)

CDCl3,300MHz 9.67(bt, 1H) 9.15(s, 1H) 8.85(s, 1H) 7.42(d, 1H, J=8.7Hz)7.2-7.3(m, 2H) 7.00(t, 2H, J=8.4Hz) 6.91(d, 1H, J=8.7Hz) 4.15(t, 2H,J=7.2Hz) 4.12(t, 2H, J=6.6Hz) 3.70(q, 2H, J=7.2Hz) 2.92(t, 2H, J=7.2Hz)1.7-1.9(m, #4H) 1.3-1.6(m, 8H) 0.95(t, 3H, J=7.2Hz) 0.95(t, 3H, J=7.2Hz)KBr 3286 1654 1520 1500 FAB+483(M + H+) (100) 344(50)

[0338] TABLE 24 Ex. comp./structure/character/mp (° C.) 1H NMR (δ) ppmIR cm⁻¹ MS

DMSO-d6,300MHz 11.22(bs, 1H) 10.10(t, 1H, J=5.8Hz) 9.66(s, 1H) 8.76(s,1H) 7.45(d, 1H, J=8.8Hz) 7.14(d, 1H, J=8.8Hz) 6.91(s, 1H) 6.87(d, 1H,J=7.9Hz) 6.82(d, 1H, J=7.9Hz) 5.99(s, 2H) 4.45(d, 2H, J=5.8Hz) 3.91(s,3H) KBr 3161 # 1655 1268 1113 1039 934 802 521 LCQ(+) 369 [M + H+](100)

DMSO-d6,300MHz 11.42(s, 1H) 9.96(t, 1H, J=5.7Hz) 8.86(s, 1H) 8.79(s, 1H)8.75(s, 1H) 7.67(d, 1H, J=9.0Hz) 7.14(d, 1H, J=9.0Hz) 6.73(d, 1H,J=3.6Hz) 6.68(d, 1H, J=8.1Hz) 6.59(dd, 1H, J=8.1, 3.6 Hz) 4.38(d, 2H,J=5.7Hz) 3.99(t, 2H, #J=6.9Hz) 3.93(s, 3H) 1.7-1.8(m, 2H) 1.3-1.4(m, 4H)0.89(t, 3H, J=7.2Hz) KBr 3246 1672 1626 1536 1260 1109 FAB+427 [M +H+](100)

DMSO-d6,300MHz 11.0(bs, 1H) 10.2(bs, 1H) 10.17(bt, 1H) 8.76(s, 1H)7.66(d, 1H, J=8.9Hz) 7.14(d, 1H, J=8.9Hz) 6.93(s, 1H) 6.74(s, 2H)4.45(d, 2H, J=5.5Hz) 3.98(t, 2H, J=6.8Hz) 3.91(s, 3H) 3.75(s, 3H)1.7-1.9(m, 2H) 1.3-1.5 #(m, 4H) 0.88(t, 3H, J=7.0Hz) KBr 3350 3193 29541920 1668 1627 1528 1464 LCQ(−) 439 [M − H+](100)

[0339] TABLE 25 Ex. comp./structure/character/mp (° C.) 1H NMR (δ) ppmIR cm⁻¹ MS

DMSO-d6,300MHz 11.45, 11.39(s, 1H) 9.9-10.1(t, 1H) 8.79, 8.79(s, 1H)6.6-6.8(bs, 1H) 7.64(d, 1H, J=8.9Hz) 7.13(d, 1H, J=8.9Hz) 6.7-7.1(m, 3H)5.63, 5.57(bs, 1H) 5.22(bs, 1H), 4.8-4.9(m, 1H, 4.44(bd, 2H) 3.98(t, 2H,J=6.9Hz) 3.93(s, #3H) 3.82(d, 1H, J=9.6Hz) 3.3-3.5(m, 4H) 1.7-1.9(m, 2H)1.3-1.5(m, 4H) 0.89(t, 3H, 7.2Hz) KBr 3396 1666 FAB+603 [M + H+](100)

DMSO-d6,300MHz 11.8(bs, 1H) 11.5(bs, 1H) 10.04(bt, 1H) 8.79(s, 1H)7.70(d, 1H, J=8.9Hz) 7.14(d, 1H, J=8.9Hz) 6.91(s, 1H) 6.86(d, 1H,J=7.9Hz) 6.82(d, 1H, J=7.9Hz) 5.98(s, 2H) 4.46(d, 2H, J=5.9Hz) 3.99(t,2H, J=6.5Hz) 3.93(s, #3H) 2.27(t, 2H, J=7.2Hz) 1.7-1.9(m, 2H) 1.6-1.7(m,2H) KBr 3300 1730 LCQ(+) 469 [M + H+](100)

DMSO-d6,300MHz 12.00(bs, 1H) 11.50(bs, 1H) 10.00(t, 1H, J=5.7Hz)8.88(bs, 1H) 8.80(s, 1H) 7.70(d, 1H, J=8.9Hz) 7.14(d, 1H, J=8.9Hz)6.93(s, 1H) 6.74(s, 2H) 4.45(d, 2H, J=5.7Hz) 3.98(t, 2H, J=6.6Hz)3.96(s, 3H) 3.75(s, #3H) 2.2-2.4(m, 2H) 1.7-1.8(m, 2H) 1.6-1.7(m, 2H)KBr 3449 1707 1686 1626 1545 1499 1263 LCQ(+) 471 [M + H+](100)

[0340] TABLE 26 Ex. comp./structure/character/mp (° C.) 1H NMR (δ) ppmIR cm⁻¹ MS

DMSO-d6,300MHz 11.45(s, 1H) 10.04(t, 1H, J=5.9Hz) 8.79(s, 1H) 7.70(d,1H, J=8.9Hz) 7.14(d, 1H, J=8.9Hz) 6.91(s, 1H) 6.87(d, 1H, J=7.9Hz)6.82(d, 1H, J=7.9Hz) 5.99(s, 2H) 4.47(d, 2H, J=5.9Hz) 4.36(t, 2H,J=5.1Hz) 3.98(t, 2H, #J=6.9Hz) 3.93(s, 3H) 3.3-3.4(m, 2H) 1.7-1.8(m, 2H)1.4-1.5(m, 4H) KBr 3300 2900 1550 LCQ(+) 455 [M + H+](100)

DMSO-d6,300MHz 11.46(s, 1H) 10.00(t, 1H, J=5.7Hz) 8.88(s, 1H) 8.80(s,1H) 7.70(d, 1H, J=8.9Hz) 7.14(d, 1H, J=8.9Hz) 6.93(s, 1H) 6.73(s, 1H)4.45(d, 1H, J=5.7Hz) 4.36(t, 1H, J=5.3Hz) 3.98(t, 2H, J=6.8Hz) 3.93(s,#3H) 3.74(s, 3H) 3.3-3.5(m, 2H) 1.7-1.9(m, 2H) 1.4-1.6(m, 4H) KBr 33921554 1260 1110 1038 801 LCQ(+) 457 [M + H+](100)

DMSO-d6,300MHz 11.47(s, 1H), 10.04(t, 1H, J=6.0Hz) 8.79(s, 1H) 7.70(d,1H, J=8.9Hz) 7.14(d, 1H, J=8.9Hz) 6.91(d, 1H, J=1.4Hz) 6.87(d, 1H,J=7.9Hz) 6.82(dd, 1H, J=7.9, 1.4Hz), 5.99(s, 2H) 4.47(d, 2H, J=6.0Hz)4.43(d, 1H, #J=4.7Hz) 3.99(t, 2H, J=6.9Hz) 3.93(s, 3H) 3.6-3.7(m, 1H)1.7-1.9(m, 2H) 1.4-1.5(m, 2H) 1.07(d, 3H, J=6.2Hz) KBr 3397 2965 16721623 1544 1501 1260 LCQ(+) 455 [M + H+](100)

[0341] TABLE 27 Ex. comp./structure/character/mp (° C.) 1H NMR (δ) ppmIR cm⁻¹ MS

DMSO-d6,300MHz 11.53(s, 1H) 10.04(t, 1H, J=5.9Hz) 8.79(s, 1H) 7.70(d,1H, J=8.9Hz) 7.14(d, 1H, J=8.9Hz) 6.91(s, 1H) 6.87(d, 1H, J=7.9Hz)6.82(d, 1H, J=7.9Hz) 5.99(s, 2H) 4.47(d, 2H, J=5.9Hz) 3.96(t, 2H,J=6.5Hz) 3.92(s, 3H) 2.64(t, 2H, J=7.2Hz) 2.13 #(s, 3H) 1.9-2.0(m, 2H)KBr 3290 2895 1707 1672 1621 1538 1440 1371 LCQ(+) 453 [M + H+](100)

DMSO-d6,400MHz 11.55(s, 1H) 10.02(bt, 1H) 8.78(s, 1H) 7.69(d, 1H,J=8.9Hz) 7.15(d, 1H, J=8.9Hz) 6.90(s, 1H) 6.87(d, 1H, J=8.0Hz) 6.82(d,1H, J=8.0Hz) 5.98(s, 2H) 4.82(bs, 1H) 4.46(d, 2H, J=5.8Hz) 4.0-4.2(2H),3.93(s, 3H), 3.58(bs, 1H) 1.8-2.0(m, #1H) 1.6-1.8(m, 1H) 1.4-1.5(m, 2H)0.88(t, 3H, J=7.4Hz) KBr 3438 1626 1110 1802 LCQ(+) 455 [M + H+](100)

DMSO-d6,300MHz 11.31(s, 1H) 10.01(bt, 1H) 8.81(s, 1H) 7.74(d, 1H,J=8.7Hz) 7.15(d, 1H, J=8.9Hz) 6.92(d, 1H, J=0.9Hz) 6.85(d, 1H, J=7.8Hz)6.82(dd, 1H, J=7.8, 0.9Hz) 5.99(s, 2H) 4.46(d, 2H, J=5.7Hz) 4.15(d, 2H,J=6.0Hz) 3.93 #(s, 3H) 3.01(t, 2H, J=5.4Hz) 2.55(q, 2H, 6.9Hz) 0.97(t,3H, J=6.9Hz) KBr 3448 1676 1534 1259 1120 805 LCQ(+) 453 [M + H+](100)

[0342] TABLE 28 Ex. comp./structure/character/mp (° C.) 1H NMR (δ) ppmIR cm⁻¹ MS

DMSO-d6,300MHz 11.47(s, 1H) 10.00(t, 1H, J=6.0Hz) 8.81(s, 1H) 7.73(d,1H, J=8.7Hz) 7.15(d, 1H, J=8.7Hz) 6.90(s, 1H) 6.87(d, 1H, J=7.8Hz)6.81(d, 1H, J=7.8Hz) 5.99(s, 2H) 5.65(bd, 1H) 4.46(d, 2H, J=6.0Hz)4.07(dd, 1H, J=9.9, 2.1Hz), 3.94(s, 3H) 3.80 #(bs, 1H) 3.6-3.7(m, 1H)1.3-1.5(m, 4H) 0.89(t, 3H, J=6.6Hz) KBr 3404 1666 1545 1264 LCQ(+) 455[M + H+](100)

CDCl3,300MHz 9.36(bs, 1H) 9.23(s, 1H) 8.88(s, 1H) 7.45(d, 1H, 9.0Hz)6.94(d, 1H, 9.0Hz) 5.86(bs, 1H) 4.14(t, 2H, J=7.2Hz) 3.98(s, 3H)1.7-1.9(m, 2H) 1.3-1.5(m, 4H) 0.95(t, 3H, J=6.9Hz) KBr 3329 3163 29561687 1500 1370 # 1300 FAB+305 [M + H+](100)

[0343] TABLE 29 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

DMSO-d6,300MHz 11.06(s, 1H) 10.30(s, 1H) 9.80(bt, 1H) 9.25(s, 1H)8.65(s, 1H) 7.29(d, 1H, J=8.6Hz) 7.2-7.4(m, 2H) 7.1-7.2(m, 2H) 6.83(d,1H, J=8.6Hz) 3.55(q, 2H, J=7.2Hz) 2.83(t, 2H, J=7.2Hz) KBr 3236 16681510 1357 1220 FAB+ # 343[M − H+](100)

CDCl3,300MHz 9.10(br s, 1H) 7.65(s, 1H) 7.26(d, J=8.0Hz, 1H) 6.86(d,J=8.0Hz, 1H) 4.65(s, 2H) 4.13(t, J=6.6Hz, 2H) 3.95(s, 3H) 1.80(m, 2H)1.50(m, 2H) 0.99(t, J=7.3Hz, 3H) KBr 3176 1651 1610 1509 1281 1111 #1063 (fab+, NBA) 278 260 (fab−, NBA) 276 199

CDCl3,300MHz 9.18(brs, 1H) 7.65(s, 1H) 7.26(d, 1HJ=8.4Hz) 6.87(d, 1H,J=8.7Hz) 4.65(s, 2H) 4.22(q, 2H, 6.9Hz) 3.95(s, 3H) 3.36(brs, 1H)1.42(t, 3H, J=6.9Hz) KBr 3434 1644 1510 1379 1283

[0344] TABLE 30 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS

CDCl3,300MHz 9.05(br s, 1H) 7.83(s, 1H) 7.33(dd, J=4.6, 8.9Hz, 2H)7.26(d, J=8.8Hz, 1H) 6.99(t, J=8.8Hz, 2H) 6.86(br s, 1H) 6.85(d,J=8.8Hz, 1H) 5.21(s, 2H) 4.11(t, J=6.8Hz, 2H) 3.94(s, 3H) 1.79(m, 2H)1.50(m, 2H) 0.99(t, J=7.7Hz, 3H) KBr # 3305 1706 1656 1611 1537 15091262 1219 1112 1077 (fab+, NBA) 415 260 (fab−, NBA) 413 276 199

DMSO-d6,300MHz 11.08(brs, 1H) 10.27(s, 1H) 8.39(d, 2H, J=6.2Hz) 7.94(s,1H) 7.44(m, 3H) 7.02(d, 1H, J=8.8Hz) 5.06(s, 2H) 4.05(q, 2H, J=7.0Hz)3.89(s, 3H) 1.31(t, 3H, J=7.0Hz) KBr 2978 1745 1659 1609 1508 # 12511209 (FAB+) 370(M + H+) (50)

CDCl3,300MHz 9.03(brs, 1H) 7.75(s, 1H) 7.26(d, 1H, J=8.8Hz) 6.84(d, 1H,J=8.8Hz) 4.20(q, 2H, J=7.0Hz) 3.94(s, 3H) 3.47(s, 2H) 2.35(s, 6H)1.41(t, 3H, J=7.0Hz) KBr 2773 1644 1605 1285 1109 FAB+277(M + H+) (100)

[0345] TABLE 31 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS 7-2

Colorless crystal/ CDCl3, 300MHz 9.00(brs, 1H) 7.65(s, 1H) 7.24(d,J=8.7H) 6.83(d, J=8.7Hz, 1H) 4.12(t, J=6.9Hz, 2H) 3.93(s, 3H) 3.82(s,2H) 1.80(m, 2H) 1.80(brs, 2H) 1.50(m, 2H) 0.99(t, J=7.3Hz, 3H) (fab+,NBA) 278 260 (fab−, NBA) 276 199 7-3

Colorless crystal/166-169 CDCl3, 300MHz 9.03(brs, 1H) 7.78(brs, 1H)7.27(d, 1H, J=8.8Hz) 6.85(d, 1H, J=8.8Hz) 4.20(q, 2H, J=7.0Hz) 3.94(s,3H) 3.78(t, 4H, 4.8Hz) 3.56(brs, 2H) 1.41(t, 3H, J=7.0Hz) KBr 2968 16561611 1280 1115 FAB+319(M + H+) (100) 8-1

Colorless crystal/207-209 DMSO-d6, 300MHz 8.75(br s, 1H) 7.70(s, 1H)7.43-7.38(m, 3H) 7.05(t, J=8.9Hz, 2H) 6.98(d, J=8.9Hz, 1H) 6.54(br t,J=5.8Hz, 1H) 4.04(d, J=5.8Hz, 2H) 3.98(t, J=6.8Hz, 2H) 3.87(s, 3H)1.75(m, 2H) 1.41(m, 2H) 0.93(t, J=7.3Hz, 3H) KBr 3313 1659 1611 15771508 1281 1216 1113

[0346] TABLE 32 Ex. No./structure/character/mp (° C.) 1H NMR (δ) ppm IRcm⁻¹ MS 8-2

Colorless crystal/199-200 DMSO-d6, 300MHz 10.72(br s, 1H) 9.24(br s, 1H)8.27(t, J=5.9Hz, 1H) 7.41(s, 1H) 7.22(d, J=8.8Hz, 1H) 7.11(d, J=8.4Hz,2H) 6.97(d, J=8.8Hz, 1H) 6.71(d, J=8.4Hz, 2H) 4.07(d, J=5.5Hz, 2H)3.97(t, J=6.6Hz, 2H) 3.87(s, 3H) 3.38(s, 2H) 1.74(m, 2H) 1.41(m, 2H)0.92(t, J=7.3Hz, 3H) KBr 3387 1648 1609 1509 1278 1260 1108

[0347] Pharmacological Experiment

[0348] (1] Binding Assay (In Vitro)

[0349] Membrane fractions of human central type cannabinoid receptor(human CB1-CHO, hereinafter called hCB1) and human peripheral typecannabinoid receptor (human CB2-CHO, hereinafter called hCB2) expressedin CHO cells were used as samples. The reference material (hCB1: 20μg/ml, hCB2: 5 μg/ml), labeled ligand ([³H]Win55212-2, 2 nM) andunlabeled ligand Win55212-2 or test compound were added to a 24-wellround bottom plate, and the plate was incubated at 30° C. for 90minutes. 50 mM Tris-HB55 containing 0.2% BSA was used as an assaybuffer. After incubation, the mixture was filtered (Packard, Unifilter24GF/B) and dried, and then a scintillation solution (Packard,Microsint-20) was added thereto to determine the radioactivity of thesample (Packard, Top count A9912V). Nonspecific binding was determinedby the addition of excessive amount of Win55212-2 (10 μM), and specificbinding was calculated by subtracting the nonspecific binding from totalbinding determined by the addition of the labeled ligand only. The testcompound was dissolved in DMSO to make the final concentration in DMSOto be 0.1%. IC₅₀ value was determined from the proportion of the boundtest compound in the specific binding, and K₁ value of the test compoundwas calculated from the IC_(so) value and K_(d) value of [³H]Win55212-2.K₁ value for the central type receptors/K₁ value for peripheral typereceptors (C/S) was also calculated as an indicator of the selectivityof the test compound for peripheral type receptors. Results are shown inTables 33 to 36. TABLE 33 Ki value (nM) Central type Peripheral typereceptor receptor Example (C) (S) C/S 1-2 3671 0.014 262202 1-4 16274.49 362 2-1 4330 8.90 487 2-2 3247 00.77 42172 2-4 905 0.032 28273 2-5434 0.20 2170 2-6 770 0.13 5923 2-7 381 0.42 908 3-1 49 0.13 ± 0.05 3723-5 3436 0.087 39497 3-6 609 0.020 30472 3-7 72 0.48 150 3-8 81 0.0194275

[0350] TABLE 34 Ki value (nM) Central type Peripheral type receptorreceptor Example (C) (S) C/S 3-14 131 0.33 396 3-15 249 0.016 15580 3-16208 0.010 20805 3-17 199 0.23 867 3-18 1751 7.10 247 3-19 49 0.18 2723-20 78 0.41 191 3-21 162 0.97 167 3-22 135 0.20 675 3-23 39 0.20 1943-25 444 1.29 344 3-26 648 0.23 2817 3-27 336 0.021 15990

[0351] TABLE 35 Ki value (nM) Central type Peripheral type receptorreceptor Example (C) (S) C/S 3-30 168 0.090 1862 3-31 159 0.16 995 3-322398 0.036 66604 3-33 273 1.06 258 3-34 172 0.011 15672 3-35 409 0.0537713 3-36 183 0.021 8695 3-37 78 0.75 104 3-38 935 0.085 11002 3-40 7032.13 330 3-41 62 0.35 176 3-42 315 0.22 1430 3-43 864 0.043 20093

[0352] TABLE 36 Ki value (nM) Central type Peripheral type receptorreceptor Example (C) (S) C/S 3-44 193 0.18 1075 3-45 381 0.032 119023-46 228 0.026 8776 5-1 686 0.45 1525 5-2 122 0.055 2219 6-1 703 0.04515612 6-2 437 0.034 12866 7-1 3643 0.17 21432 7-3 666 0.062 10735 8-1440 0.44 1000 8-2 727 0.27 2692

[0353] [2] Carrageenin-Induced Paw Edema Model (in vivo)

[0354] C57BL/6J mice (6 to 8 weeks of age) were used. The volume of theright hind paw before administration was measured (Unicom,Prethysumometter TK-101), and 2 hours later, the test compound dissolvedin olive oil was administered orally at 10 ml/kg. After one hour of theadministration, 50 μl of 1% solution of carrageenin in normal saline wasadministered intradermally at foot pad of the right hind paw., Threehours later, the volume of the right hind paw was measured and comparedwith the initial volume. Results are shown in Table 37. TABLE 37 ED₅₀ED₆₀ Example (mg/kg; p.o.) Example (mg/kg; p.o.) 3-5 <0.10 3-26 1.32 3-90.58 3-27 0.53 3-11 0.40 3-30 0.49 3-15 0.41 3-37 0.63 3-17 1.39 3-382.24 3-22 0.76 3-40 1.19

[0355] [3] The compounds of the invention were shown to significantlyinhibit inflammation and hemorrhage in the pancreas, in the experimentsusing pancreatitis model induced by taurocholic acid in rats.

[0356] An example of formulation is shown below, but is not intended tolimit the present invention.

[0357] Example of Formulation

[0358] (a) The compound of Example 1-1: 10 g

[0359] (b) Lactose: 50 g

[0360] (c) Maize starch: 15 g

[0361] (d) Carboxymethylcellulose sodium: 44 g

[0362] (e) Magnesium stearate: 1 g

[0363] All of (a), (b) and (c), and 30 g of (d) were kneaded with water,and the mixture was dried in vacuo and then granulated. To this granularpowder, 14 g of (d) and 1 g of (e) were mixed, and the mixture wastableted by a tablet maker to manufacture 1000 tablets containing 10 mgof (a) in a tablet.

[0364] Industrial Applicability

[0365] The compound [I] of the present invention and itspharmaceutically acceptable salts selectively act on cannabinoidreceptors, particularly on peripheral type cannabinoid receptors, andhave fewer side effects on the central nervous system, having greatimmunomodulating action, anti-inflammatory action and antiallergicaction. Therefore, these compounds are useful as cannabinoid receptor(particularly peripheral cannabinoid receptors) regulator,immunomodulators, therapeutic agent for autoimmune diseases,anti-inflammatory agents, and antiallergic agents.

1. A cannabinoid receptor modulator comprising, as an active ingredient,a 2-oxoquinoline compound represented by the following general formula[I] or its pharmaceutically acceptable salt:

where W means —O—, —S(O)_(t)—, —CR³R⁴—, —NR⁵—, —NR⁵CO—, —CONR⁵—, —COO—or —OCO— (where R³ and R⁴ may be identical or different and representhydrogen atom or alkyl; R⁵ represents hydrogen atom or alkyl; and tindicates an integer, 0, 1 or 2); R¹ represents hydrogen atom, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or cycloalkylalkyl; each group of R¹, except hydrogen atom,may be substituted or unsubstituted with alkylamino, amino, hydroxy,alkoxy, carboxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto,alkylthio, alkylsulfinyl or alkylsulfonyl; each group, except hydrogenatom and alkyl, may be substituted or unsubstituted with alkyl; R²represents hydrogen atom, alkyl, —OR⁶ (where R⁶ represents hydrogenatom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl or cycloalkylalkyl), —NR⁷R⁸ (where R⁷ and R⁸may be identical or different and represent hydrogen atom, alkyl,alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or cycloalkylalkyl; or R⁷ and R⁸, together with the adjacentnitrogen atom, can form a heteroaryl); or —(CH₂)_(u)′—S(O)_(u)R⁹ (whereR⁹ represents hydrogen atom, alkyl, alkenyl or alkynyl, each of u and u′independently represents an integer, 0, 1 or 2); each group of R²,except hydrogen atom, may be substituted or unsubstituted withalkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy,acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl; eachgroup, except hydrogen atom and alkyl, may be substituted orunsubstituted with alkyl; R^(a) represents hydrogen atom or alkyl; Xrepresents —COOR^(b), —CONH₂, —CONR^(c)-(Alk^(a))_(r)-R,—(CH₂)_(p)—OC(═Y)—NR^(d)- (Alk^(b))_(g)-R,—(CH₂)_(q)—NR^(e)—C(=z)-(NR^(f))_(w)-(Alk^(c))_(v)-R, —(CH₂)_(p)—OH or—(CH₂) _(q)—NR^(e)R^(e)′ (where each of R^(b), R^(c), R^(d), and R^(f)independently represents hydrogen atom or alkyl; each of R^(e) andR^(e)′ independently represents hydrogen atom or alkyl; or R^(e) andR^(e)′, together with the adjacent nitrogen atom, can form a heteroaryl;each of Alk^(a), Alk^(b) and Alk^(c) independently represents alkyleneor alkenylene; each of the alkylene and alkenylene may be substituted orunsubstituted with hydroxy, carboxy, alkoxycarbonyl, alkyl (the alkylmay be substituted or unsubstituted with hydroxy, alkoxy or alkylthio)or —CONR¹⁰R¹¹ (where R¹⁰ and R¹¹ may be identical or different andrepresent hydrogen atom or alkyl; or R¹⁰ and R¹¹, together with theadjacent nitrogen atom, can form a heteroaryl); R represents aryl,heteroaryl, cycloalkyl, benzene-condensed cycloalkyl or

where A and B independently represent oxygen atom, nitrogen atom orsulfur atom; k indicates an integer of 1-3; each of the aryl andheteroaryl may be substituted or unsubstituted with an alkyl substitutedor unsubstituted with hydroxy or may be substituted or unsubstitutedwith a hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro,amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino,carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronicacid residue; the cycloalkyl may be substituted or unsubstituted with ahydroxy, alkoxy or ═O; the benzene-condensed cycloalkyl may besubstituted or unsubstituted with a hydroxy or alkoxy; each of r, s, vand w independently represents 0 or 1; each of Y and Z independentlyrepresents a nitrogen atom, oxygen atom or sulfur atom; and each of pand q independently represents an integer of 1-4).
 2. A cannabinoidreceptor modulator comprising, as an active ingredient, the2-oxoquinoline compound of claim 1 or its pharmaceutically acceptablesalt, wherein W represents —O—; R¹ is hydrogen atom or alkyl (the alkylis as described above); R² represents —OR⁶ (R⁶ is as described above) ;and R is aryl, heteroaryl or

where aryl, heteroaryl, and each symbol in this formula are as definedabove.
 3. A 2-oxoquinoline compound as represented by the followinggeneral formula [I′] or its pharmaceutically acceptable salt:

where W means —O—, —S(O)_(t)—, —CR³R⁴—, —NR⁵—, —NR⁵CO—, —CONR⁵—, —COO—or —OCO— (where R³ and R⁴ may be identical or different and representhydrogen atom or alkyl; R⁵ represents hydrogen atom or alkyl; and tindicates an integer, 0, 1 or 2); R¹ represents hydrogen atom, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or cycloalkylalkyl; each group of R¹, except hydrogen atom,may be substituted or unsubstituted with alkylamino, amino, hydroxy,alkoxy, carboxy, alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto,alkylthio, alkylsulfinyl or alkylsulfonyl; each group, except hydrogenatom and alkyl, may be substituted or unsubstituted with alkyl; R²represents hydrogen atom, alkyl, —OR⁶ (where R⁶ represents hydrogenatom, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl or cycloalkylalkyl), —NR⁷R⁸ (where R⁷ and R⁸may be identical or different and represent hydrogen atom, alkyl,alkenyl, alkynyl, acyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl or cycloalkylalkyl; or R⁷ and R⁸, together with the adjacentnitrogen atom, can form a heteroaryl); or —(CH₂)_(u)′—S(O)_(u)R⁹ (whereR⁹ represents hydrogen atom, alkyl, alkenyl or alkynyl, each of u and u′independently represents an integer, 0, 1 or 2); each group of R²,except hydrogen atom, may be substituted or unsubstituted withalkylamino, amino, hydroxy, alkoxy, alkoxycarbonyl, acyl, acyloxy,acylthio, mercapto, alkylthio, alkylsulfinyl or alkyl sulfonyl; eachgroup, except hydrogen atom and alkyl, may be substituted orunsubstituted with alkyl; Ra represents hydrogen atom or alkyl; X′represents —CONR^(c)-(Alk^(a))_(r)-R,—(CH₂)_(p)—OC(═y)—NR^(d)-(Alk^(b))_(a)-R or—(CH₂)_(q)—NR^(e)—C(=Z)-(NR^(f))_(w)-(Alk^(c))_(v)-R, where each of R^(c), R^(d), R^(e) andR^(f) independently represents hydrogen atom or alkyl; each of Alk^(a),Alk^(b)and Alk^(c) independently represents alkylene or alkenylene; eachof the alkylene and alkenylene may be substituted or unsubstituted withhydroxy, carboxy, alkoxycarbonyl, alkyl (the alkyl may be substituted orunsubstituted with a hydroxy, alkoxy or alkylthio); or —CONR¹⁰R¹¹ (whereR¹⁰ and R¹¹ may be identical or different and represent hydrogen atom oralkyl; or R¹⁰ and R¹¹, together with the adjacent nitrogen atom, canform a heteroaryl); R represents aryl, heteroaryl, cycloalkyl,benzene-condensed cycloalkyl or

where A and B independently represent oxygen atom, nitrogen atom orsulfur atom; k indicates an integer of 1-3; each of the aryl andheteroaryl may be substituted or unsubstituted with an alkyl substitutedor unsubstituted with hydroxy or may be substituted or unsubstitutedwith a hydroxy, alkoxy, alkenyloxy, acyl, acyloxy, halogen atom, nitro,amino, sulfonamide, alkylamino, aralkyloxy, pyridyl, piperidino,carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, cyano or glucuronicacid residue; the cycloalkyl may be substituted or unsubstituted with ahydroxy, alkoxy or ═O; the benzene-condensed cycloalkyl may besubstituted or unsubstituted with a hydroxy or alkoxy; each of r, s, vand w independently represents 0 or 1; each of Y and Z independentlyrepresents a nitrogen atom, oxygen atom or sulfur atom; and each of pand q independently represents an integer of 1-4, provided that: (a)when R² is a hydrogen atom, then WR¹ is substituted at position-j of2-oxoquinoline; and (b)1,2-dihydro-6,7-dimethoxy-2-oxo-N-(phenylmethyl)-3-quinolinecarboxamideand N-(1,2-dihydro-6,7-dimethoxy-2-oxo-3-quinolyl) benzamide areexcluded.
 4. The 2-oxoquinoline compound of claim 3 or itspharmaceutically acceptable salt, wherein X′ is—CONR^(c)-(Alk^(a))_(r)-R.
 5. The 2-oxoquinoline compound of claim 3 orits pharmaceutically acceptable salt, wherein X′ is—(CH₂)_(p)—OC(═Y)—NR^(d)-(Alk^(b))_(s)-R or—(CH₂)_(q)—NR^(e)—C(=Z)-(NR^(f))_(w)-(Alk^(c))_(v)-R.
 6. The2-oxoquinoline compound of any one of claims 3 to 5 or itspharmaceutically acceptable salt, wherein R is aryl, heteroaryl or

where aryl, heteroaryl, and each symbol in the formula are as definedabove.
 7. The 2-oxoquinoline compound of any one of claims 3 to 5 or itspharmaceutically acceptable salt, wherein R is

where each symbol is as defined above.
 8. The 2-oxoquinoline compound ofany one of claims 3 to 7 or its pharmaceutically acceptable salt,wherein W is —O— and R² is —OR⁶ (where R⁶ is a hydrogen atom or alkyl).9. The 2-oxoquinoline compound of any one of claims 3 to 8 or itspharmaceutically acceptable salt, wherein the substitution position ofWR¹ is position-j of the benzene ring, and the substitution position ofR² is position-i of the benzene ring
 10. The 2-oxoquinoline compound ofany one of claims 3, 4, and 6 to 9 or its pharmaceutically acceptablesalt, wherein Alk^(a) is alkylene and r=1.
 11. The 2-oxoquinolinecompound of any one of claims 3 to 10 or its pharmaceutically acceptablesalt, wherein the 2-oxoquinoline compound is selected from the groupconsisting of7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-aminobenzyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-aminophenyl)ethyl]amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-aminophenyl)amide hydrochloride,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl)amide,8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-hydroxyphenyl)ethyl]amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-pyridylmethyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-piperidinoethyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-morpholinoethyl) amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(3-pyridylmethyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-pyridylmethyl)amide,8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(2-phenylethyl)amide,8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide, 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide,8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide hydrochloride,8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(2-fluorophenyl)ethyl]amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(3-fluorophenyl)ethyl]amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-hydroxy-3-methoxyphenyl)ethyl]amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-chlorophenyl)ethyl]amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-phenylethyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-methylbenzyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-fluorobenzyl)amide,7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid(2-pyridine-4-ylethyl)amide,7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide,7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-hydroxyphenyl)ethyl]amide,7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl)amide,7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid(2-phenylethyl)amide,7,8-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide,7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide,7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl)amide,7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(2-morpholinoethyl) amide,8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl)amide,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid [2-(4-fluorophenyl)ethyl]amide,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-pyridine-4-ylethyl)amide,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-morpholinoethyl)amide,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (4-pyridylmethyl)amide,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (4-fluorobenzyl)amide,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid [2-(4-hydroxyphenyl)ethyl]amide,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide,1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid [2-(4-fluorophenyl)ethyl]amide,1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (2-morpholinoethyl)amide,1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide,7,8-dipentyloxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide,8-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid(3,4-methylenedioxybenzyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(3,4-dihydroxybenzyl)amide,7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid(4-hydroxy-3-methoxybenzyl)amide,1-0-{2-hydroxy-5-[(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-3-quinolyl)carbonylaminomethyl]phenyl}glucosidouronicacid,1-0-{2-hydroxy-4-[(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-3-quinolyl)carbonylaminomethyl]phenyl}glucosidouronicacid,5-[7-methoxy-3-{(3,4-methylenedioxybenzyl)carbamoyl)-2-oxo-1,2-dihydro-8-quinolyloxy]pentanoicacid,5-[7-methoxy-3-{(3-hydroxy-4-methoxybenzyl)carbamoyl}-2-oxo-1,2-dihydro-8-quinolyloxy]pentanoicacid,8-(5-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide,8-(5-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (4-hydroxy-3-methoxybenzyl)amide,8-(4-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide,7-methoxy-2-oxo-8-(4-oxopentyloxy)-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide,8-(3-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide,7-methoxy-2-oxo-8-(3-oxopentyloxy)-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide,8-(2-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylicacid (3,4-methylenedioxybenzyl)amide,7,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid[2-(4-fluorophenyl)ethyl]amide,8-butoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline,8-ethoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline,N-(4-fluorophenyl)carbamic acid(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl ester,N-pyridine-4-ylcarbamic acid(8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl ester,3-dimethylaminomethyl-8- ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline,8-butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline,8-ethoxy-7-methoxy-3-morpholinomethyl-2-oxo-1,2-dihydroquinoline,N-[(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N′-(4-fluorophenyl)ureaandN-[(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-(4-hydroxyphenyl)acetamide.12. A 2-oxoquinoline compound or its pharmaceutically acceptable salt,the 2-oxoquinoline compound being selected from the group consisting of7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acidmethyl ester,7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acidmethyl ester,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester and1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid methyl ester.
 13. A 2-oxoquinoline compound or its pharmaceuticallyacceptable salt, the 2-oxoquinoline compound being selected from thegroup consisiting of7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid,8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid,8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid,7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid,7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid,1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid and1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylicacid.
 14. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamideor its pharmaceutically acceptable salt
 15. A pharmaceutical compositioncomprising, as an active ingredient, the 2-oxoquinoline compound of anyone of claims 3 to 14 or its pharmaceutically acceptable salt.
 16. Acannabinoid receptor modulator comprising, as an active ingredient, the2-oxoquinoline compound of any one of claims 3 to 14 or itspharmaceutically acceptable salt.
 17. A peripheral cannabinoid receptormodulator comprising, as an active ingredient, the 2-oxoquinolinecompound of any one of claims 3 to 14 or its pharmaceutically acceptablesalt, the 2-oxoquinoline compound selectively acting on peripheral typecannabinoid receptors.
 18. The 2-oxoquinoline compound of any one ofclaims 3 to 14 or its pharmaceutically acceptable salt, wherein the2-oxoquinoline compound is an immunomodulator, therapeutic agent forautoimmune diseases, antiallergic agent, or antiinflammatory agent. 19.The 2-oxoquinoline compound of any one of claims 3 to 14 or itspharmaceutically acceptable salt, wherein the 2-oxoquinoline compound isan antiinflammatory agent.
 20. An antiinflammatory agent comprising, asan active ingredient, the 2-oxoquinoline compound of claim 1 or 2 or itspharmaceutically acceptable salt.